CD3 binding molecules and related methods and uses

Abstract

Provided are binding molecules that bind to CD3, in particular, binding molecules that incorporate human antibodies, including antibody fragments, specific for CD3. In some aspects, the provided binding molecules are bispecific antibodies directed to CD3 and a second antigen, such as a B cell antigen or a tumor antigen. Also provided are polynucleotides that encode the binding molecules, including the antibodies or bispecific antibodies. Also provided are pharmaceutical compositions and methods and uses of such binding molecules for treatment of diseases in which specific targeting, and in some aspects T-cell-mediated killing, of cells that express the second antigen is desired.

Description

217372000540CD3 BINDING MOLECULES AND RELATED METHODS AND USES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. provisional application No. 63 / 747,480, filed January 21, 2025, entitled “CD3 BINDING MOLECULES AND RELATED METHODS AND USES”, the contents of which are incorporated by reference in their entirety.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 217372000540. xml created January 17, 2026, which is 189,388 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.FIELD OF DISCLOSURE

[0003] The present disclosure relates in some aspects to binding molecules that bind to CD3 and in particular, binding molecules that incorporate human antibodies, including antibody fragments, specific for CD3. In some aspects, among the binding molecules of the present disclosure are bispecific antibodies directed to CD3 and a second antigen, such as a B cell antigen or a tumor antigen. The disclosure further relates to polynucleotides that encode the binding molecules, including the antibodies or bispecific antibodies. The present disclosure further relates to pharmaceutical compositions, kits and methods and uses of such binding molecules for treatment of diseases in which specific targeting, and in some aspects T-cell-mediated killing, of cells that express the second antigen is desired.BACKGROUND

[0004] Binding molecules, including bispecific antibodies, that target CD3 on T cells have been used as a T cell engager (TCE) to recruit cytolytic T cells to kill tumor cells. In many cases, CD3-targeting antibodies are high-affinity antibodies which can favor their binding to circulating T cells or in secondary lymphoid organs. This may limit their use due to issues such as unfavorable pharmacokinetics and non-specific binding leading to activation of peripheral T cells in a tumor-target independent fashion. Improved CD3 binding molecules are needed including for use in a TCE.217372000540SUMMARY

[0005] An aspect of the invention provides a binding molecule comprising a CD3 binding domain comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein: the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1) set forth in SEQ ID NO: 1, a heavy chain complementarity determining region 2 (CDR-H2) set forth in SEQ ID NO: 2, and a heavy chain complementarity determining region 3 (CDR-H3) set forth in SEQ ID NO:3; and the VL region comprises a light chain complementarity determining region 1 (CDR-L1) set forth in SEQ ID NO: 19, a light chain complementarity determining region 2 (CDR-L2) set forth in SEQ ID NO: 5, and a light chain complementarity determining region 3 (CDR-L3) set forth within SEQ ID NO: 6.

[0006] In certain embodiments, the VH region comprises an amino acid sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD X4SKX5YYADSVKGRFTISRDNSX6NTLX7LQMNSLRAEDTAVYYCARSNYDILTX8X9 YX10X11GX12X13VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is G or C; X4is G or A; X5is K, T, or D; X6is K, E, or S; X7is Y or D; X8is R or G; X9is Y or H; X10 is Q or S; Xu is Y or H; X12 is I or L; and X13 is N or D; (SEQ ID NO:7); and the VL region comprises an amino acid sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLEXiGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX2SYPRTFGX3GTKVEIK, wherein Xi is N or S; X2is K or N; X3is Q or C; (SEQ ID NO:8).

[0007] In certain embodiments, the VH region comprises an amino acid sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD ASKX4YYADSVKGRFTISRDNSX5NTLYLQMNSLRAEDTAVYYCARSNYDILTX6X7Y X8X9GX10X11VWGQGTTVTVSS, wherein Xi=R or G or E; X2=R or N; X3=G or C; X4=K or T or D; X5=K or E or S; X6=R or G; X7=Y or H; X8=Q or S; X9=Y or H; Xio= I or L; and Xn=N or D (SEQ ID NO: 83); and the VL region comprises an amino acid sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX1SYPRTFGX2GTKVEIK (SEQ ID NO:84), wherein Xi=K or N; and X2=Q or C.217372000540

[0008] In certain embodiments, the binding molecule is a bispecific antibody comprising the CD3 binding domain and a second antigen binding domain. In certain embodiments, the second antigen binding domain comprises a means for binding a second antigen wherein the second antigen is on a tumor or a B cell.

[0009] An aspect of the invention provides a binding molecule comprising a CD3 binding domain and a second antigen binding domain, wherein the binding molecule is bispecific for binding CD3 and the second antigen, wherein: (a) the CD3 binding domain comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein: the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1) set forth in SEQ ID NO: 1, a heavy chain complementarity determining region 2 (CDR-H2) set forth in SEQ ID NO: 2, and a heavy chain complementarity determining region 3 (CDR-H3) set forth in SEQ ID NO:3, and the VL region comprises a light chain complementarity determining region 1 (CDR-L1) set forth in SEQ ID NO: 19, a light chain complementarity determining region 2 (CDR-L2) set forth in SEQ ID NO: 5, and a light chain complementarity determining region 3 (CDR-L3) set forth within SEQ ID NO: 6; and

[0010] In certain embodiments, the VH region comprises a CDR-H1 set forth in SEQ ID NO: 1, a CDR-H2 set forth in SEQ ID NO: 85, and a CDR-H3 set forth in SEQ ID NO:3; and the VL region comprises a CDR-L1 set forth in SEQ ID NO: 19, a CDR-L2 set forth in SEQ ID NO: 22, and a CDR-L3 set forth within SEQ ID NO: 6.

[0011] In certain embodiments, the VH region comprises an amino acid sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD X4SKX5YYADSVKGRFTISRDNSX6NTLX7LQMNSLRAEDTAVYYCARSNYDILTRYY X8X9GX10X11VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is G or C; X4is G or A; X5 is K, T, or D; Xe is K, E, or S; X7 is Y or D; Xs is Q or S; X9 is Y or H; X10 is I or L; Xu is N or D; (SEQ ID NO:7); and the VL region comprising an amino acid sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLEXiGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX2SYPRTFGX3GTKVEIK, wherein Xi is N or S; X2is K or N; X3is Q or C ; (SEQ ID NO:8).

[0012] In certain embodiments, the VH region comprises an amino acid sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD ASKX4YYADSVKGRFTISRDNSX5NTLYLQMNSLRAEDTAVYYCARSNYDILTX6X7Y217372000540XsXgGXioXnVWGQGTTVTVSS, wherein Xi=R or G or E; X2=R or N; X3=G or C; X4=K or T or D; X5=K or E or S; X6=R or G; X7=Y or H; X8=Q or S; X9=Y or H; Xio= I or L; and Xn=N or D (SEQ ID NO: 83); and the VL region comprises an amino acid sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX1SYPRTFGX2GTKVEIK (SEQ ID NO:84), wherein Xi=K or N; and X2=Q or C.

[0013] In certain embodiments, the CD3 binding domain binds to CD3 epsilon with a dissociation constant (KD) of 5 nM or more.

[0014] In certain embodiments, the CD3 binding domain binds to CD3 epsilon with a dissociation constant (KD) of 10 nM to 70 nM.

[0015] In certain embodiments, the VH comprises one or more amino acid residues selected from the group consisting of: an asparagine (N) at position 31 , an alanine (A) at position 55, a tyrosine (Y) at position 80, a glycine (G) at position 106, a histidine (H) at position 107, a serine (S) at position 109, a histidine (H) at position 110, a leucine (E) at position 112, and an aspartic acid (D) at position 113 or any combination thereof, wherein the numbering is relative to SEQ ID NO: 24.

[0016] In certain embodiments, the VH comprises: (a) amino acid residues asparagine (N) at position 31, alanine (A) at position 55, and tyrosine (Y) at position 80, wherein the numbering is relative to SEQ ID NO: 24; (b) alanine (A) at position 55, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 24; or (c) alanine (A) at position 55, tyrosine (Y) at position 80, serine (S) at position 109, and histidine (H) at position 110, wherein the numbering is relative to SEQ ID NO: 24.

[0017] In certain embodiments, the VL region comprises one or more amino acid residues selected from the group consisting of: a serine (S) at position 56, an asparagine (N) at position 92, and a cysteine (C) at position 100, an asparagine (N) at position 108, or any combination thereof, wherein the numbering is relative to SEQ ID NO: 39.

[0018] In certain embodiments, the VL region comprise: (a) serine (S) at position 56, wherein the numbering is relative to SEQ ID NO:39; or (b) serine (S) at position 56 and asparagine (N) at position 92, wherein the numbering is relative to SEQ ID NO: 39.

[0019] In certain embodiments, the CD3 binding domain exhibits low polyreactivity to extracellular matrix proteins.217372000540

[0020] In certain embodiments, the CD3 binding domain exhibits an extracellular matrix (ECM) score of less than 14, less than 13, less than 12, less than 11, or less than 10.

[0021] In certain embodiments, the VH comprises glycine (G) at position 16, a glutamic acid (E) at position 16, a threonine (T) at position 58, an aspartic acid (D) at position 58, a glutamic acid (E) at position 76, a serine (S) at position 76 in relation to SEQ ID NO: 24.

[0022] In certain embodiments, the VH comprises glycine (G) at position 16 and / or threonine (T) at position 58, optionally glycine (G) at position 16 and threonine (T) at position 58 in relation to SEQ ID NO: 24.

[0023] In certain embodiments, the CD3 binding domain is an antigen binding antibody fragment. In some embodiments, the CD3 binding domain is selected from the group consisting of Fab, Fab', F(ab')2, Fv, and scFv. In some embodiments, the CD3 binding domain is a Fab. In some embodiments, the CD3 binding domain is a scFv or is an Fv. In certain embodiments, the CD3 binding domain is an scFv that is a disulfide- stabilized scFv. In some of any embodiments, the antigen-binding fragment is an scFv. In some embodiments, the scFv comprises a VH-linker-VL arrangement. In some embodiments, the scFv comprises a VL-linker-VH arrangement. In some of any embodiments, the linker is a peptide linker comprising (Gly4Ser)3 (SEQ ID NO: 96) In some of any embodiments, the linker is a peptide linker comprising Gly4Ser (SEQ ID NO: 94). In some of any embodiments, the linker is a peptide linker comprising (Gly4Ser)2 (SEQ ID NO: 95).

[0024] In certain embodiments, the VH region CD3 binding domain comprises cysteine (C) at position 44 and the VL region of the CD3 binding domain comprises a cysteine (C) at position 100 in relation to SEQ ID NO: 39.

[0025] In certain embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within any one of SEQ ID NOs: 24-38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within any one of SEQ ID NOs: 39-43.

[0026] In certain embodiments, the CDR-H1 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9 or 12, the CDR-H2 comprises the sequence set forth in any one of SEQ ID NOs: 10, 13, 15, or 17, and the CDR-H3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 11, 14, 16, or 18; and the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NOs: 19, the CDR-L2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 20 or 22, and the CDR-L3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 21 or 23.217372000540

[0027] In certain embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 28, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 42; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 29, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 30, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 31, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 32, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 33, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 34, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within217372000540SEQ ID NO: 38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41; or the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 126, and the VL region comprises the CDR-Ll, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40.

[0028] In certain embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 12, 13, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 14, respectively, and the VL region comprises the CDR-Ll, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 16, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 17, and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 18, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively.

[0029] In certain embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an217372000540amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 25, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 26, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 28, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 42; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 29, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 30, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43; the VH region comprises an amino acid sequence that217372000540has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 32, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 33, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 34, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 38, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41; or the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 126, and the VL region comprises an amino acid sequence that has at least at or217372000540about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40.

[0030] In certain embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 39, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 25 and 40, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 26 and 40, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 27 and 41, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 28 and 42, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 29 and 40, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 30 and 41, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 31 and 43, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 32 and 40, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 33 and 40, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 34 and 40, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 35 and 40, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 40, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 37 and 40, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 38 and 41, respectively; or the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 126 and 40, respectively.

[0031] In certain embodiments, the CD3 binding domain comprises the VH region that comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 14, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively.

[0032] In certain embodiments, the CD3 binding domain comprises the VH region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 28, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 42.217372000540

[0033] In certain embodiments, the CD3 binding domain comprises the VH region and the VL region that comprises the sequence or are the sequence set forth in SEQ ID NO: 28 and 42, respectively.

[0034] In certain embodiments, the CD3 binding domain comprises the VH region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 40.

[0035] In certain embodiments, the CD3 binding domain comprises the VH region and the VL region that comprises the sequence or are the sequence set forth in SEQ ID NO: 29 and 40, respectively.

[0036] In certain embodiments, the CD3 binding domain comprises the VH region that comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 16, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively.

[0037] In certain embodiments, the CD3 binding domain comprises the VH region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 30, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41.

[0038] In certain embodiments, the CD3 binding domain comprises the VH region and the VL region that comprises the sequence or are the sequence set forth in SEQ ID NO: 30 and 41, respectively.

[0039] In certain embodiments, the CD3 binding domain comprises the VH region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 31, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43.

[0040] In certain embodiments, the CD3 binding domain comprises the VH region and the VL region that comprises the sequence or are the sequence set forth in SEQ ID NO: 31 and 43, respectively.217372000540

[0041] An aspect of the invention provides a binding molecule comprising a CD3 binding domain comprising a VH region and a VL region, wherein: the VH region comprises a CDR-H1 set forth in SEQ ID NO: 107, a CDR-H2 set forth in SEQ ID NO: 154, and a CDR-H3 set forth in SEQ ID NO: 109; and the VL region comprises a CDR-L1 set forth in SEQ ID NO: 19, a CDR-L2 set forth in SEQ ID NO: 110, and a CDR-L3 set forth within SEQ ID NO: 155.

[0042] An aspect of the invention provides a binding molecule comprising a CD3 binding domain comprising a VH region and a VL region, wherein: the VH region comprises a CDR-H1 set forth in SEQ ID NO: 107, a CDR-H2 set forth in SEQ ID NO: 108, and a CDR-H3 set forth in SEQ ID NO: 109; and the VL region comprises a CDR-L1 set forth in SEQ ID NO: 19, a CDR-L2 set forth in SEQ ID NO: 110, and a CDR-L3 set forth within SEQ ID NO: 6.

[0043] In certain embodiments, the VH region of the CD3 binding domain and the VL region of the CD3 binding domain comprises, respectively: an amino acid sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2X3GIHWVRQAPGKX4LEWVAAIWY DX5SX6X7YYADSVKGRFTISRDNSX8NTLX9LQMNSLRAEDTAVYYCARSNX10DX11L TX12X13YX14X15GX16X17VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is Y or H, X4is G orC; X5is G, A, or S; X6is K, H, or N, X7is K, T, or D; X8is K, E, or S; X9is Y or D; X10 is Y or F, Xu is I or V, X12 is R or G; X13 is Y or H; X14 is Q or S; X15 is Y or H; Xi6 is I or L; and X17 is N or D; (SEQ ID NO: 156); and an amino acid sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASX1LEX2G VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX3SYPRTFGX4GTKVEIK, wherein Xi is S or G, X2is N or S; X3is K or N; and X4is Q or C; (SEQ ID NO: 106).

[0044] The binding molecule of any one of claims 1-3, wherein the VH region of the CD3 binding domain and the VL region of the CD3 binding domain comprises, respectively: an amino acid sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2X3GIHWVRQAPGKX4LEWVAAIWY DX5SX6X7YYADSVKGRFTISRDNSX8NTLX9LQMNSLRAEDTAVYYCARSNX10DX11L TX12X13YX14X15GX16X17VWGQGTTVTVSS, wherein Xi is R, G, or E; X2 is R or N; X3is Y or H, X4is G or C; X5is G or A or S; X6is K, H, or N, X7is K, T, or D; X8is K, E, or S; X9 is Y or D; X10 is Y or F, Xu is I or V, X12 is R or G; X13 is Y or H; X14 is Q or S; X15 is Y or H; Xi6 is I or L; and X17 is N or D; (SEQ ID NO: 105); and sequence of the consensus sequence set forth in217372000540AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASX1LEX2G VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX3SYPRTFGX4GTKVEIK, wherein Xi is S or G, X2is N or S; X3is K or N; and X4is Q or C; (SEQ ID NO: 106).

[0045] In certain embodiments, the CDR-H1 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9, 12, 111, or 112, the CDR-H2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 10, 13, 15, 17, or 113-117 , and the CDR-H3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 11, 14, 16, 18, 118-123; and the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NOs: 19, the CDR-L2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 20, 22, 124, or 125, and the CDR-L3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 21 or 23.

[0046] In certain embodiments, in the CD3 binding region: the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 28, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 42; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 29, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 30, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 31, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 32, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 33, and the VL217372000540region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 34, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 126, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 4, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 53, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 54, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 55, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 56, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 57, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 58, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 59, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3217372000540contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 60, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 61, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 62, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 63, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 64, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 65, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 66, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 67, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 68, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 69, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 70, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 71, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 72, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 73, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3217372000540contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 74, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 75, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 40; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 77; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 78; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 79; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 80; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39; or the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39.

[0047] In certain embodiments, the VH region of the CD3 binding domain and the VL region of the CD3 binding domain comprises: the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 12, 13, and 11, respectively, and t the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 13, and21737200054014, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 13, and 11, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 15, and 14, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 15, and 16, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 17, and 14, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 15, and 18, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 113, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 13, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 114, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 115, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid217372000540sequence set forth in SEQ ID NOs: 9, 10, and 118, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 18, respectively, and VL region the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 119, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 120, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 16, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 12, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 111, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 112, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 121, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 122, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 123, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3217372000540comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 14, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 116, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 117, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 13, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 18, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 13, and 119, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 111, 13, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 113, and 123, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 23, respectively; the CDR-H1, CDR-H2 and the CDR-H3217372000540comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 124, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOs: 19, 125, and 23, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 16, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 12, 13, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; or the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 14, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively.

[0048] In certain embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 25, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 26, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least217372000540at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 28, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 42; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 29, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 30, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 32, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 33, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 34, and the VL region comprises an amino acid sequence that has at least at or about 85%,21737200054086%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 38, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 126, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 4, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 53, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%,21737200054087%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 54, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 55, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 56, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 57, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 58, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 59, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 60, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 61, and the VL region217372000540comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 62, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 63, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 64, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 65, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 66, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 67, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 68, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,21737200054094%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 69, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 70, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 71, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 72, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 73, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 74, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 75, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41; the VH region comprises an amino acid217372000540sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 99; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 100; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 101; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39; or the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 26, and the VL region comprises an amino acid sequence that has at217372000540least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39.

[0049] In certain embodiments, in the CD3 binding domain: the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 24 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 24 and 40, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 26 and 40, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 27 and 41, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 28 and 42, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 29 and 40, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 30 and 41, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 31 and 43, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 32 and 40, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 33 and 40, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 34 and 40, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 35 and 40, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 36 and 40, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 37 and 40, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 38 and 41, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 126 and 40, respectively; VH region and the VL region comprise the sequences set forth in SEQ ID NO: 4 and 39, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 83 and 39, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 54 and 39, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 55 and 39, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 56 and 39, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 57 and 39, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 58 and 39, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 59 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 76 and 39,1217372000540respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 61 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 62 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 63 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 64, and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 65 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 66 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 67 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 68 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 69 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 70 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 71 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 72 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 73 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 74 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 75 and 39, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 24 and 40, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 24 and 77, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 24 and 81, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 24 and 79, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 24 and 80, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 27 and 39, respectively; the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 39, respectively; or the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 26 and 39, respectively.

[0050] In certain embodiments, the binding molecule is a full length antibody. For example, the full length antibody comprises a constant region (Fc) from an IgAl, IgA2, IgD, IgE, IgGl, IgG2, IgG3, IgG4, or IgM. In certain embodiments, the constant region is a human IgGl heavy chain constant region. In certain embodiments, the constant region217372000540comprises the amino acid sequence set forth in any of SEQ ID NOs: 44-47. In certain embodiments, the constant region comprises the amino acid sequence set forth in any of SEQ ID NO: 48-51.

[0051] In certain embodiments, the binding molecule comprises an amino acid sequence described herein including those containing sequences listed in Table E2, Table E3, Table E4, and / or Table E12. In certain embodiments, the binding molecule comprises an amino acid sequence listed in the Examples 1-7.

[0052] Provided herein is a polynucleotide comprising a nucleic acid sequence(s) encoding the binding molecule or antibody or antigen-binding fragment disclosed herein. An aspect of the invention provides a binding molecule comprising an amino acid sequence described herein. An aspect of the invention provides a polynucleotide comprising a nucleic acid encoding a binding molecule described herein. In certain embodiments, the nucleic acid encodes a binding molecule comprising an amino acid sequence described herein including those containing sequences listed in Table E2, Table E3, Table E4, and / or Table E12. In certain embodiments, the nucleic acid encodes a binding molecule listed in the Examples 1-7.

[0053] An aspect of the invention provides a vector comprising any of the polynucleotides described herein. In some embodiments, the vector is an expression vector. In certain embodiments, the vector is a viral vector. For example, the viral vector is a retroviral vector or a lentiviral vector. In some embodiments, the vector useful for expressing a binding molecule described herein comprising the polynucleotide.

[0054] An aspect of the inventions provides a cell comprising any of the polynucleotides described herein, or any of the vectors of described herein. In certain embodiments, the cell is a mammalian cell. In certain embodiments, the cell is a CHO cell. In certain embodiments, the cell is a NS0 cell. In certain embodiments, the cell is a SP2 / 0 cell. In certain embodiments, the cell is a HEK293 cell. In certain embodiments, the cell is a PER.C6 cell. In certain embodiments, the cell is a BHK-21 cell.

[0055] An aspect of the invention provides a method of producing any of the antibodies described herein comprising culturing the cell under a condition that produces the antibody. In certain embodiments, the method, further comprises recovering the antibody produced by the cell.

[0056] An aspect of the inventions provides an antibody or antigen-binding fragment thereof produced by any of the methods described herein.

[0057] An aspect of the invention provides a composition comprising any of the binding molecules described herein. In certain embodiments, the binding molecule comprises an217372000540amino acid sequence described herein including any containing sequences listed in Table E2, Table E3, Table E4, and / or Table E12. In certain embodiments, the binding molecule comprises an amino acid sequence listed in the Examples 1-7. In certain embodiments, the composition further comprises a pharmaceutically acceptable excipient.

[0058] An aspect of the invention provides a method for treating a subject with a disease or condition, the method comprising administering a therapeutically effective amount of any of the binding molecules described herein. In certain embodiments, the binding molecule comprises an amino acid sequence described herein including any containing sequences listed in Table E2, Table E3, Table E4, and / or Table E12. In certain embodiments, the binding molecule comprises an amino acid sequence listed in the Examples 1-7.

[0059] In certain embodiments, wherein the disease or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer. In certain embodiments ,the disease or condition is a tumor or a cancer.

[0060] An aspect of the invention provides a kit comprising any of the binding molecules described herein and, optionally, instructions for use.DETAILED DESCRIPTION

[0061] Provided are CD3-binding molecules, such as anti-CD3 antibodies including antigen-binding antibody fragments that specifically bind to CD3 proteins, such as a human CD3 protein. The binding molecules also include proteins that include any of the provided anti-CD3 antibodies, including bispecific antibodies. In particular embodiments, provided are bispecific T cell engaging antibodies that bind and target CD3 and a second antigen to mediate specific targeting and T cell-mediated killing of cells that express the second antigen. Also provided are polynucleotides containing nucleic acids sequences encoding all or a portion of such binding molecules, including polynucleotides that encode polypeptide chains of the bispecific antibodies. Among the provided embodiments are approaches for targeting cells expressing the second antigen useful in the treatment of diseases and conditions, including cancers or autoimmune diseases or conditions.

[0062] The human CD3 T cell antigen receptor protein complex is composed of six distinct chains: a CD3y chain (SwissProt P09693), a CD36 chain (SwissProt P04234), two CD3e chains (SwissProt P07766), and one CD3(^ chain homodimer (SwissProt P20963) (sy:s8: Q, which is associated with the T cell receptor a and P chain. This complex plays an important role in coupling antigen recognition to several intracellular signal-transduction217372000540pathways. The CD3 complex mediates signal transduction, resulting in T cell activation and proliferation. CD3 is required for immune response. Among provided embodiments, the binding molecules target or bind CD3 epsilon (CD3e or CD3e). In some embodiments, the antibodies provided herein bind to human CD3e set forth in SEQ ID NO:82.

[0063] Therapies targeting CD3 that specifically engage T cells for cytolytic killing of target cells are needed. Such therapies include TCE bispecific antibody therapies for targeted killing of antigen-expression cells. Among TCE therapies are therapies that direct T cells to tumors that selectively recruit T cells to tumor cells such that the targeted antibody therapy delivers cytotoxic cells specifically to the antigen-expressing cancer cells. Similar approaches are useful for targeting autoreactive T and / or B cells in connection with autoimmune diseases or indications.

[0064] Yet, TCE approaches have not been entirely satisfactory. In many instances, current therapies may exhibit undesired tonic signaling either in the absence of a second target antigen or due to high affinity binding to CD3 on T cells. This risk of tonic signaling may exacerbate the chance of toxicides, such as cytokine release syndrome (CRS), to the antigen-directed therapy. CRS is a concern for T cell modality therapies including T cell engagers. While on target T cell killing of tumor cells results in cytokine release, tonic signaling and cytokine release of T cells through CD3 binding independent of tumor associated antigen binding is not desired. Improved strategies are needed for optimal responses to antibody or T cell-mediated therapies. Provided are embodiments that meet such needs.

[0065] Among the provided embodiments are CD3 binding molecules that include an anti-CD3 antibody or antigen-binding fragment. In some aspects, provided binding molecules contain a detuned anti-CD3 targeting domain that has reduced affinity to CD3 compared to other T cell engagers, thereby minimizing risks of tonic signaling and CRS. Also among the provided embodiments are T cell engager bispecific antibodies directed against CD3 and a second antigen that is expressed on a target cell desired to be targeted for cytolytic killing. In some embodiments, the target cell is a tumor or cancer cell. In some embodiments, the target cell is an autoreactive B cell. Due to the lower affinity, and in some cases low tonic signaling, the provided binding molecules, including bispecific antibodies, are promising candidates for engaging T cell activity including in connection with mediating cytolytic killing of antigen-expressing cells.

[0066] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to217372000540the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0067] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.I. DEFINITIONS

[0068] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art

[0069] As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. In each instance herein any of the terms "comprising," "consisting essentially of," and "consisting of" may be optionally replaced with either of the other two terms, thus describing alternative aspects of the scope of the subject matter. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.

[0070] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The use of "or" or "and" means "and / or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include," "includes," and "included," is not limiting.

[0071] The term "about" as used herein when referring to a measurable value such as an amount, a temporal duration and the like, encompasses variations of up to ± 10% from the specified value. Unless otherwise indicated, all numbers expressing e.g., quantities of217372000540ingredients or properties (e.g., molecular weight, reaction conditions) described herein are to be understood as being modified by the term "about".

[0072] As used herein, “and / or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” includes “A and B,” “A or B,” “A” alone, and “B” alone. Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” encompasses each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A alone; B alone; and C alone.

[0073] As used herein, recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. For example, if a concentration range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3% are expressly enumerated in this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between and including the lowest value and the highest value enumerated are to be considered to be expressly stated in this disclosure.

[0074] The term “binding domain” characterizes in connection with the present disclosure a domain which (specifically) binds to / interacts with / recognizes a given target epitope or a given target side on the target molecules (antigens), e.g., CD3. The structure and function of the first binding domain (recognizing CD3), and preferably also the structure and / or function of the second binding domain (such as those described in section II.B.l), is / are based on the structure and / or function of an antibody, e.g. of a full-length or whole immunoglobulin molecule and / or is / are drawn from the variable heavy chain (VH) and / or variable light chain (VL) domains of an antibody or fragment thereof. Typically, the first binding domain is characterized by the presence of three light chain CDRs (i.e. CDR1, CDR2 and CDR3 of the VL region) and / or three heavy chain CDRs (i.e. CDR1, CDR2 and CDR3 of the VH region). The second binding domain typically also comprises the minimum structural requirements of an antibody which allow for the target binding. More typically, the second binding domain comprises at least three light chain CDRs (i.e. CDR1, CDR2 and CDR3 of the VL region) and three heavy chain CDRs (i.e. CDR1, CDR2 and CDR3 of the VH region).

[0075] The term “antibody” as used herein is used in the broadest sense and includes polyclonal and monoclonal antibodies, including intact antibodies and functional (antigenbinding) antibody fragments, including fragment antigen binding (Fab) fragments, F(ab’)z217372000540fragments, Fab’ fragments, Fv fragments, recombinant IgG (rlgG) fragments, heavy chain variable (VH) regions capable of specifically binding the antigen, single chain antibody fragments, including single chain variable fragments (scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragments. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific or trispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, tandem tri-scFv. Unless otherwise stated, the term “antibody” should be understood to encompass functional antibody fragments thereof also referred to herein as “antigen-binding fragments.” The term also encompasses intact or full-length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD.

[0076] In some embodiments, the antibody constructs of the invention are “isolated” or “substantially pure” antibody constructs. “Isolated” or “substantially pure”, when used to describe the antibody constructs disclosed herein, means an antibody construct that has been identified, separated and / or recovered from a component of its production environment. Preferably, the antibody construct is free or substantially free of association with all other components from its production environment. Contaminant components of its production environment, such as that resulting from recombinant transfected cells, are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. The antibody constructs may e.g. constitute at least about 5%, or at least about 50% by weight of the total protein in a given sample. It is understood that the isolated protein may constitute from 5% to 99.9% by weight of the total protein content, depending on the circumstances. The polypeptide may be made at a significantly higher concentration through the use of an inducible promoter or high expression promoter, such that it is made at increased concentration levels. The definition includes the production of an antibody construct in a wide variety of organisms and / or host cells that are known in the art. In preferred embodiments, the antibody construct will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Ordinarily, however, an isolated antibody construct will be prepared by at least one purification step.217372000540

[0077] An antigen-binding site of an antibody provided herein contains six CDRs which contribute in varying degrees to the affinity of the binding site for antigen. There are three heavy chain variable domain CDRs (referred to as CDR-H1, CDR-H2 and CDR-H3) and three light chain variable domain CDRs (referred to as CDR-L1, CDR-L2 and CDR-L3). A skilled artisan is familiar with CDR and framework regions (FRs) of antibodies, and can determine the boundaries of such regions using various known schemes.

[0078] The terms “complementarity determining region,” and “CDR,” synonymous with “hypervariable region” or “HVR,” are known to refer to non-contiguous sequences of amino acids within antibody variable regions, which confer antigen specificity and / or binding affinity. In general, there are three CDRs in each heavy chain variable region (z.e., CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (z.e., CDR-L1, CDR-L2, CDR-L3). “Framework regions” and “FR” are known to refer to the non-CDR portions of the variable regions of the heavy and light chains. In general, there are four FRs in each full-length heavy chain variable region (z.e., FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in each full-length light chain variable region (i.e., FR-L1, FR-L2, FR-L3, and FR-L4).

[0079] The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat etal. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme); Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48 (“Chothia” numbering scheme); MacCallum et al., J. Mol. Biol, 1996; 262:732-745.” (“Contact” numbering scheme); Lefranc MP et al., Dev Comp Immunol, 2003; 27(l):55-77 (“IMGT” numbering scheme); Honegger A and Pliickthun A, J Mol Biol, 2001; 309(3):657-70, (“Aho” numbering scheme); Martin et al., PNAS, 1989; 86(23):9268-9272, (“AbM” numbering scheme); and Ye et al., Nucleic Acids Res. 2013; 41(Web Server issue):W34-40, (“IgBLAST numbering scheme). Details regarding various numbering schemes are also described in, for example, Jarasch et al., Proteins, 2017; 85(l):65-71 ; Martin et al., Bioinformatics tools for antibody engineering. In: Diibel, S.(editor) Handbook of Therapeutic Antibodies, Vol. 1. Wiley- VCH, Weinheim, Germany; Martin, A.C.R. (2010). Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Kontermann, R., Diibel, S. (eds) Antibody Engineering. Springer Protocols Handbooks. Springer, Berlin, Heidelberg, and Martin, ACR, Antibody Information: How to identify the CDRs by looking at a sequence [online] <http: / / www.bioinf.org.uk / abs / info.html>, all of which are incorporated by reference in their entireties. Various prediction algorithm tools are available and known for numbering217372000540antibody residues and CDRs (e.g., AbYsis, Abnum, AbYmod, AbRSA, IgBLAST, IMGT, or ANARCI).

[0080] The boundaries of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignments, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, in some cases with insertions. Insertions in the sequence relative to the standard numbering scheme are indicated using insertion letter codes. For example, residues that are inserted between residues L30 and L31 are indicated as L31A, L31B, etc. Deletions in the sequence relative to the standard scheme are accommodated by skipping numbers. The two schemes place certain insertions and deletions (“indels”) at different positions, resulting in differential numbering. For instance, the Chothia numbering scheme is nearly identical to the Kabat numbering scheme, except that insertions are placed at structural positions and topologically equivalents residues do get assigned the same numbers. The Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme. The AbM scheme is a compromise between Kabat and Chothia definitions based on that used by Oxford Molecular’s AbM antibody modeling software. The IgBLAST scheme is based on matching to germline V, D and J genes, and can be determined using National Center for Biotechnology Information (NCBI)’s IgBLAST tool.

[0081] In some embodiments, reference to CDRs herein is by Kabat numbering. In some embodiments, Kabat numbering can be determined by known sequence rules as described in, for example, Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Svice, National Institutes of Health, Bethesda, MD. In some embodiments, the Kabat numbering scheme in some aspects can include any of the following rules to designate CDRs: CDR-L1 starts at approximately residue 24 of the light chain, always has a preceding C residue, and always has a following W residue; the end of CDR-L1 is defined by a stretch of 3 residues, where the W residue can be followed by Y, L, or F, followed by Q or L; CDR-1 has a length of 10 to 17 residues; CDR-L2 always starts 16 residues after the end of CDR-L1; the two residues before CDR-L2 are I and Y but can also be V and Y, I and K, or I and F; CDR-L2 is always 7 residues long; CDR-L3 always starts 33 residues after the end of CDR-L2, always has a preceding C residue, and is strictly followed by a F-G-X-G sequence motif, where X is any amino acid; CDR-L3 has a length of 7 to 11 residues; CDR-H1 starts at approximately position 26 of the heavy chain; the first amino acid in CDR-H1 is always 9 residues after a conserved C residue; CDR-H1 is followed by an invariant W residue217372000540followed by V, I, or A; CDR-H1 has a length of 5 to 7 residues; CDR-H2 always starts at 15 residues after the end of CDR-H1; the first residue in CDR-H2 is usually preceded by the sequence motif L-E-W-I-G but a number of variations exist; the end of CDR-H2 is defined by a motif of 3 residues - the first residue of the motif of 3 residues can be either K or R, the second residue of the motif of 3 residues can be L, I, V, F, T, or A, the third residue of the motif of 3 residues can be T, S, I, or A; CDR-H2 has a length of 16 to 19 residues; CDR-H3 always starts 33 residues after the end of CDR-H2 and is always 3 residues after a C residue -the first residue of CDR-H3 is preceded by the conserved C residue followed by two residues, which are usually A-R; the residues following CDR-H3 is strictly followed by a W-G-X-G sequence motif, where the X is any amino acid; CDR-H3 typically has a length of 3 to 25 residues; CDR-H3 can be much longer than 25 residues.

[0082] In some embodiments, reference to CDRs herein is by Chothia numbering. In some cases, according to the Chothia numbering scheme, exact boundary positions of certain CDRs can differ based on different definitions for the CDRs (See e.g., Martin, ACR, Antibody Information: How to identify the CDRs by looking at a sequence [online] <http: / / www.bioinf.org.uk / abs / info.html>). For example, in some instances, the boundary positions for CDR-F1 according to Chothia numbering can be F26-F32 (Chothia et al., Science, 1986; 233(4765):755-8 and Chothia C. and Desk A.M. J Mol Biol, 1987;196(4):901- 17). In some instances, the boundary positions for CDR-F1 can be F25-F32 (Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48). In some instances, the boundary positions for CDR-F2 can be L50— F52 and for CDR-F3 can be L91— F96 (Chothia et al., Science, 1986; 233(4765):755-8; Chothia C. and Desk A.M. J Mol Biol, 1987; 196(4):901- 17; Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48). In some instances, the boundary positions for CDR-H1 according to Chothia numbering can be H26-H32 (Chothia et al., Science, 1986; 233(4765):755-8; Chothia C. and Desk A.M. J Mol Biol, 1987; 196(4):901- 17; Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48). In some instances, the boundary positions for CDR-H2 can be H53-H55 (Chothia et al., Science, 1986; 233(4765):755-8 and Chothia C. and Desk A.M. J Mol Biol, 1987, 196(4):901- 17); H52a-H55 (Tramontane et al., J Mol Biol, 1990, 215(1): 175-82). In some instances, the boundary positions for CDR-H2 can be H52-H56 (Al-Fazikani et al., J Mol Biol., 1997; 273(4):927-48). In some instances, the boundary positions for CDR-H3 can be H96-H101 (Chothia et al., Science, 1986;233(4765):755-8 and Chothia C. and Desk A.M. J Mol Biol., 1987; 196(4):901- 17). In some instances, the boundary positions for CDR-H3 can be H92-H104 (Morea et al., Biophys Chem, 1997; 68(1-3): 9-16 and Morea etal., J Mol Biol., 1998; 275(2): 269-94).217372000540

[0083] Table 1, below, lists exemplary position boundaries of CDR-L1, CDR-L2, CDR-L3 and CDR-H1, CDR-H2, CDR-H3 as identified by Kabat, Chothia, AbM, and Contact schemes, respectively. For CDR-H1, residue numbering is listed using both the Kabat and Chothia numbering schemes. FRs are located between CDRs, for example, with FR-L1 located before CDR-L1, FR-L2 located between CDR-L1 and CDR-L2, FR-L3 located between CDR-L2 and CDR-L3 and so forth. It is noted that because the shown Kabat numbering scheme places insertions at H35A and H35B, the end of the Chothia CDR-H1 loop when numbered using the shown Kabat numbering convention varies between H32 and H34, depending on the length of the loop.1 - Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD2 - Al-Lazikani et al., (1997) JMB 273,927-948

[0084] Thus, unless otherwise specified, a “CDR” or “complementary determining region,” or individual specified CDRs (e.g., CDR-H1, CDR-H2, CDR-H3), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) complementary determining region as defined by any of the aforementioned schemes, or other known schemes. For example, where it is stated that a particular CDR (e.g., a CDR-H3) contains the amino acid sequence of a corresponding CDR in a given VH or VL region amino acid sequence, it is understood that such a CDR has a sequence of the corresponding CDR (e.g., CDR-H3) within the variable region, as defined by217372000540any of the aforementioned schemes, or other known schemes. In some embodiments, the provided binding molecule, e.g., an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2, and a CDR-H3 as contained within a given VH region amino acid sequence and defined by any of the aforementioned schemes, such as Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known schemes, and a CDR-L1, a CDR-L2, and a CDR-L3 as contained within a given VL region amino acid sequence and defined by any of the aforementioned schemes, such as Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known schemes. In some embodiments, specific CDR sequences are specified. In some embodiments, specific CDR sequences are specified. Exemplary CDR sequences of provided antibodies are described using various numbering schemes (see e.g. Table 1), although it is understood that a provided antibody can include CDRs as described according to any of the other aforementioned numbering schemes or other known numbering schemes.

[0085] Likewise, unless otherwise specified, a FR or individual specified FR(s) e.g., FR-Hl, FR-H2, FR-H3, FR-H4), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) framework region as defined by any of the known schemes. In some instances, the scheme for identification of a particular CDR, FR, or FRs or CDRs is specified, such as the CDR as defined by the Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known schemes. In other cases, the particular amino acid sequence of a CDR or FR is given.

[0086] As used herein, the term "framework" or "FR" residues refers to those variable domain residues other than the hypervariable region residues defined herein as CDR residues. Unless otherwise specified, a FR or individual specified FR(s) (e.g., FR-H1, FR-H2, FR-H3, FR-H4), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) framework region as defined by any of the known schemes. In some instances, the scheme for identification of a particular CDR, FR, or FRs or CDRs is specified, such as the CDR as defined by the Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known schemes. In other cases, the particular amino acid sequence of a CDR or FR is given.

[0087] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable regions of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs. (See, e.g., Kindt et al. Kuby Immunology, 6th ed., W.H.217372000540Freeman and Co., page 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0088] Among the provided antibodies are antibody fragments. An “antibody fragment” or “antigen-binding fragment” refers to a molecule other than an intact or full-length antibody that comprises a portion of an intact or full-length antibody that binds the antigen to which the intact antibody binds. The term thus refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., human CD3). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antibody fragments include but are not limited to Fv, Fab, Fab’, Fab’-SH, F(ab’)2; diabodies; linear antibodies; VH regions, single-chain antibody molecules such as scFvs and single-domain antibodies comprising only the VH region; and multispecific antibodies formed from antibody fragments. In some embodiments, the antibody is or comprises an antibody fragment comprising a VH and a VL region. In some embodiments, the antibodies are single-chain antibody fragments comprising a heavy chain variable VH region and / or a VL region, such as Fvs or scFvs. In some embodiments, the antibodies are Fab composed of an entire light chain (i.e. VL region and a constant light chain (CL)) and the VH region and the first constant domain of one heavy chain (CHI).

[0089] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells. For instance, papain digestion of full-length antibodies produces two identical antigenbinding fragments, called "Fab" fragments, and a residual "Fc" fragment, a designation reflecting the ability to crystallize readily. Pepsin treatment of an antibody yields a single large F(ab')2 fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CHI domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known. In some embodiments, the antibodies are recombinantly-produced fragments. For instance, the chains of an antibody or antigen-binding fragment can217372000540be incorporated into an expression vector and expressed from a host cell to produce the antibody. In some instances, a recombinantly-produced antibody fragments also can include fragments comprising arrangements that do not occur naturally, such as those with two or more antibody regions or chains joined by synthetic linkers, e.g., peptide linkers, and / or that are may not be produced by enzyme digestion of a naturally- occurring intact antibody. In some aspects, the antibody fragments are scFvs. For example, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody. Antigen-binding portions can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins.

[0090] The term “human antibody”, “human antibody construct” and “human binding domain” includes antibodies, antibody constructs and binding domains having antibody regions such as variable and constant regions or domains which correspond substantially to human germline immunoglobulin sequences known in the art, including, for example, those described by Kabat et al. (1991) (loc. cit.). The human antibodies, antibody constructs or binding domains of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or side-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs, and in particular, in CDR3. The human antibodies, antibody constructs or binding domains can have at least one, two, three, four, five, or more positions replaced with an amino acid residue that is not encoded by the human germline immunoglobulin sequence. The definition of human antibodies, antibody constructs and binding domains as used herein, however, also contemplates “fully human antibodies”, which include only non- artificially and / or genetically altered human sequences of antibodies as those can be derived by using technologies or systems such as the Xenomouse. Preferably, a “fully human antibody” does not include amino acid residues not encoded by human germline immunoglobulin sequences.

[0091] Furthermore, the definition of the term “antibody construct” includes monovalent, bivalent and polyvalent / multivalent constructs and, thus, bispecific constructs, the latter which specifically bind to only two antigenic structures, as well as polyspecific / multispecific constructs, which specifically bind more than two antigenic structures, e.g. three, four or217372000540more, through distinct binding domains. Moreover, the definition of the term “antibody construct” includes molecules consisting of only one polypeptide chain as well as molecules consisting of more than one polypeptide chain, which chains can be either identical (homodimers, homotrimers or homo oligomers) or different (heterodimer, heterotrimer or heterooligomer). Examples for the above identified antibodies and variants or derivatives thereof are described inter alia in Harlow and Lane, Antibodies a laboratory manual, CSHL Press (1988) and Using Antibodies: a laboratory manual, CSHL Press (1999), Kontermann and Diibel, Antibody Engineering, Springer, 2nd ed. 2010 and Little, Recombinant Antibodies for Immunotherapy, Cambridge University Press 2009.

[0092] The term “bispecific” as used herein refers to an antibody construct that comprises at least a first binding domain and a second binding domain, wherein the first binding domain binds to one antigen or target (e.g., CD3 as disclosed herein), and the second binding domain binds to another antigen or target (e.g., a second antigen, such as those described in Section II.B.l). Accordingly, antibody constructs according to the invention comprise specificities for at least two different antigens or targets. A bispecific antibody can be a monoclonal antibody that has binding specificity for two different epitopes. Bispecific antibodies can be prepared as full length antibodies or antibody fragments. Given that the antibody constructs are (at least) bispecific, they do not occur naturally and they are markedly different from naturally occurring products. A “bispecific” antibody construct or immunoglobulin is hence an artificial hybrid antibody or immunoglobulin having at least two distinct binding sides with different specificities. Bispecific antibody constructs can be produced by a variety of methods including fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai & Lachmann, Clin. Exp. Immunol. 79:315-321 (1990).

[0093] The term “target cell surface antigen” refers to an antigenic structure expressed by a cell and which is present at the cell surface such that it is accessible for an antibody construct as described herein. It may be a protein, preferably the extracellular portion of a protein, and / or a carbohydrate structure, preferably a carbohydrate structure of a protein, such as a glycoprotein. It is preferably a tumor antigen.

[0094] As used herein, "administering" refers to the physical introduction of a CD3 binding molecule, such as an anti-CD3 antibody, antigen binding portion thereof, bispecific molecule, multispecific molecule or a nucleic acid or expression vector as described herein encoding the same, alone or in combination with another therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Preferred routes of administration for antibodies described herein include intravenous, intraperitoneal,217372000540intramuscular, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intra-lymphatic, intralesional, intracapsular, intra-orbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. Alternatively, an antibody described herein can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0095] The terms “treat,” “treating,” and “treatment,” as used herein, refer to any type of intervention or process performed on, or administering an active agent (e.g., an anti-CD3 binding molecule, such as an anti-CD3 antibody and anti-CD3 bispecific antibody, including antibody fragments thereof) to the subject with the objective of preventing, reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease. Treatment can be of a subject having a disease or a subject who does not have a disease (e.g., for prophylaxis).

[0096] As used herein, the term “subject” includes any human or non-human animal. For example, the methods and compositions described herein can be used to treat a subject having a B cell disorder. The term “non-human animal” includes all vertebrates, e.g., a mammals and non-mammals, such as non-human primates, sheep, cats, dogs, cows, chickens, amphibians, and reptiles.

[0097] The terms “detection” or “detected”, as used herein refer to qualitative and / or quantitative detection (measuring levels) with or without reference to a control.

[0098] The term “diagnosing”, as used herein, means the determination of the nature of a medical condition intended to identify a pathology which affects the subject from a number of collected data.

[0099] The terms “(specifically) binds to”, (specifically) recognizes”, “is (specifically) directed to”, and “(specifically) reacts with” mean in accordance with this invention that a binding domain interacts or specifically interacts with a given epitope or a given target side on the target molecules (antigens), e.g., CD3 as disclosed herein.217372000540

[0100] The term “epitope” refers to a side on an antigen to which a binding domain, such as an antibody or immunoglobulin, or a derivative, fragment or variant of an antibody or an immunoglobulin, specifically binds. An “epitope” is antigenic and thus the term epitope is sometimes also referred to herein as “antigenic structure” or “antigenic determinant”. Thus, the binding domain is an “antigen interaction side”. Said binding / interaction is also understood to define a “specific recognition”.

[0101] “Epitopes” can be formed both by contiguous amino acids or non-contiguous amino acids juxtaposed by tertiary folding of a protein. A “linear epitope” is an epitope where an amino acid primary sequence comprises the recognized epitope. A linear epitope typically includes at least 3 or at least 4, and more usually, at least 5 or at least 6 or at least 7, for example, about 8 to about 10 amino acids in a unique sequence.

[0102] A “conformational epitope”, in contrast to a linear epitope, is an epitope wherein the primary sequence of the amino acids comprising the epitope is not the sole defining component of the epitope recognized (e.g., an epitope wherein the primary sequence of amino acids is not necessarily recognized by the binding domain). With regard to recognition of conformational epitopes, the binding domain recognizes a three-dimensional structure of the antigen, preferably a peptide or protein or fragment thereof (in the context of the present invention, the antigenic structure for one of the binding domains is comprised within the target cell surface antigen protein). For example, when a protein molecule folds to form a three-dimensional structure, certain amino acids and / or the polypeptide backbone forming the conformational epitope become juxtaposed enabling the antibody to recognize the epitope. Methods of determining the conformation of epitopes include, but are not limited to, x-ray crystallography, two-dimensional nuclear magnetic resonance (2D-NMR) spectroscopy and site-directed spin labelling and electron paramagnetic resonance (EPR) spectroscopy.

[0103] “Appreciable affinity” includes binding with an affinity of about 106M (KD) or stronger. Preferably, binding is considered specific when the binding affinity is about 1012to 10 M, 1012to 109M, 1012to 10l0M, 10 " to 10-8M, preferably of about 10 " to lO^M. Whether a binding domain specifically reacts with or binds to a target can be tested readily by, inter alia, comparing the reaction of said binding domain with a target protein or antigen with the reaction of said binding domain with proteins or antigens other than the CD3.Preferably, a binding domain of the invention does not essentially or substantially bind to proteins or antigens other than CD3 (i.e., the first binding domain is not capable of binding to proteins other than CD3). It is an envisaged characteristic of the antibody constructs according to the present invention to have superior affinity characteristics in comparison to217372000540other HLE formats. Such a superior affinity, in consequence, suggests a prolonged half-life in vivo. The longer half-life of the antibody constructs according to the present invention may reduce the duration and frequency of administration which typically contributes to improved patient compliance. This is of particular importance as the antibody constructs of the present invention are particularly beneficial for highly weakened or even treatment resistant B cell disorder patients.

[0104] The term “does not essentially / substantially bind” or “is not capable of binding” means that a binding domain of the present invention does not bind a protein or antigen other than the CD3 and the second antigen as described in Section II B 1, i.e., does not show reactivity of more than 30%, preferably not more than 20%, more preferably not more than 10%, particularly preferably not more than 9%, 8%, 7%, 6% or 5% with proteins or antigens other than CD3 and the second antigen, whereby binding to CD3 or the second antigen, respectively, is set to be 100%.

[0105] As used herein, “isotype” refers to the antibody class (e.g., IgG (including IgGl, IgG2, IgG3, and IgG4), IgM, IgA (including IgAl and IgA2), IgD, and IgE antibody) that is encoded by the heavy chain constant region genes of the antibody.

[0106] An antibody may be from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM. The IgG isotype is divided in subclasses in certain species: IgGl, IgG2, IgG3 and IgG4 in humans, and IgGl, IgG2a, IgG2b and IgG3 in mice. Immunoglobulins, e.g., IgGl, exist in several allotypes, which differ from each other in at most a few amino acids.

[0107] As used herein, the term “allotype” refers to naturally occurring variants within a specific isotype group, where the variants differ in a few amino acids. Anti- antibodies described herein can be of any allotype. The mutation of certain residues would modulate (i.e., eliminate or decrease) the binding of the antibodies to Fey receptors and / or Clq, and thus reduce activator efficacy of the Fc domain of the IgG component of an antibody.

[0108] For nucleic acids, the term “substantial homology” indicates that two nucleic acids, or designated sequences thereof, when optimally aligned and compared, are identical, with appropriate nucleotide insertions or deletions, in at least about 80% of the nucleotides, usually at least about 80% to 85%, 85% to 90% or 90% to 95%, and more preferably at least about 98% to 99.5% of the nucleotides. Alternatively, substantial homology exists when the segments will hybridize under selective hybridization conditions, to the complement of the strand. For polypeptides, the term “substantial homology” indicates that two polypeptides, or designated sequences thereof, when optimally aligned and compared, are identical, with217372000540appropriate amino acid insertions or deletions, in at least about 80% of the amino acids, usually at least about 80% to 85%, 85% to 90%, 90% to 95%, and more preferably at least about 98% to 99.5% of the amino acids.

[0109] The percent identity between two sequences is a function of the number of identical positions shared by the sequences (z.e., % identity = # of identical positions / total # of positions x 100), considering the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.

[0110] The percent identity between two nucleotide sequences can be determined using the GAP program in the GCG software package (available at http: / / www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. The percent identity between two nucleotide or two amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller (CAB IOS, 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM 120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

[0111] The term “monoclonal antibody” (mAb) or monoclonal antibody construct as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and / or post-translation modifications (e.g., isomerizations, amidations) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic side or determinant on the antigen, in contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed against different determinants (or epitopes). The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. A monoclonal antibody may be made by a variety of techniques, including but not limited to generation from a hybridoma, recombinant DNA methods, phage-display and other antibody display methods.217372000540

[0112] The term “amino acid” or “amino acid residue” typically refers to an amino acid having its art recognized definition such as an amino acid selected from the group consisting of: alanine (Ala or A); arginine (Arg or R); asparagine (Asn or N); aspartic acid (Asp or D); cysteine (Cys or C); glutamine (Gin or Q); glutamic acid (Glu or E); glycine (Gly or G); histidine (His or H); isoleucine (He or I): leucine (Leu or L); lysine (Lys or K); methionine (Met or M); phenylalanine (Phe or F); pro line (Pro or P); serine (Ser or S); threonine (Thr or T); tryptophan (Trp or W); tyrosine (Tyr or Y); and valine (Vai or V), although modified, synthetic, or rare amino acids may be used as desired. Generally, amino acids can be grouped as having a nonpolar side chain (e.g., Ala, Cys, He, Leu, Met, Phe, Pro, Vai); a negatively charged side chain (e.g., Asp, Glu); a positively charged sidechain (e.g., Arg, His, Lys); or an uncharged polar side chain (e.g., Asn, Cys, Gin, Gly, His, Met, Phe, Ser, Thr, Trp, and Tyr).

[0113] Amino acid modifications include, for example, deletions from, and / or insertions into, and / or substitutions of, residues within the amino acid sequences of the antibody constructs. Any combination of deletion, insertion, and substitution is made to arrive at the final construct, provided that the final construct possesses the desired characteristics. The amino acid changes also may alter post-translational processes of the antibody constructs, such as changing the number or position of glycosylation sites.

[0114] For example, 1, 2, 3, 4, 5, or 6 amino acids may be inserted, substituted or deleted in each of the CDRs (of course, dependent on their length), while 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 25 amino acids may be inserted, substituted or deleted in each of the FRs. Preferably, amino acid sequence insertions into the binding molecule or antibody construct include amino- and / or carboxyl-terminal fusions ranging in length from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 residues to polypeptides containing a hundred or more residues, as well as intra-sequence insertions of single or multiple amino acid residues. Corresponding modifications may also performed within the third domain of the antibody construct of the invention. An insertional variant of the antibody construct of the invention includes the fusion to the N-terminus or to the C-terminus of the antibody construct of an enzyme or the fusion to a polypeptide.

[0115] The term “polypeptide” as used herein describes a group of molecules, which usually consist of more than 30 amino acids. Polypeptides may further form multimers such as dimers, trimers and higher oligomers, i.e., consisting of more than one polypeptide molecule. Polypeptide molecules forming such dimers, trimers etc. may be identical or nonidentical. The corresponding higher order structures of such multimers are, consequently, termed homo- or heterodimers, homo- or heterotrimers etc. An example for a217372000540hereteromultimer is an antibody molecule, which, in its naturally occurring form, consists of two identical light polypeptide chains and two identical heavy polypeptide chains. The terms “peptide”, “polypeptide” and “protein” also refer to naturally modified peptides / polypeptides / proteins wherein the modification is affected e.g. by post-translational modifications like glycosylation, acetylation, phosphorylation and the like. A “peptide”, “polypeptide” or “protein” when referred to herein may also be chemically modified such as pegylated. Such modifications are well known in the art and described herein below.IL CD3 BINDING MOLECULES

[0116] Provided are CD3-binding molecules containing an antibody binding domain that binds CD3 (also called anti-CD3 antibodies), including chimeric or bispecific molecules containing the same. Such antibody binding domains specifically bind to CD3 epsilon (CD3e) proteins, such as a human CD3e protein. Among the CD3-binding molecules are or include antibodies (including antigen-binding fragments). In some embodiments, the antibodies or antigen-binding fragments include a heavy chain variable region (VH) and a light chain variable region (VL), including full-length antibodies as well as functional antigen-binding fragments such as Fabs or single chain Fv fragments (scFvs). The antibodies include antibodies that specifically bind to CD3e, e.g., human CD3e. Among the provided anti-CD3 antibodies are human antibodies, or antibodies that are modified from or variant of human antibodies. The antibodies include isolated antibodies.

[0117] Also among the binding molecules are polypeptides containing such antibodies, including bispecific antibodies. The CD3-binding molecules that incorporate the provided antibodies e.g., antigen-binding antibody fragments) specifically bind to CD3e, such as human CD3e protein. Among the provided bispecific molecules are TCEs that incorporate an anti-CD3 antibody or antigen-binding fragment and antibody for specific targeting of T cells and a binding domain with means for binding an antigen on the surface of a tumor cell (also called a tumor- associated antigen or TAA).

[0118] In some aspects, the CD3-binding molecules include isolated molecules.

[0119] Also provided are polynucleotides containing nucleic acids sequences encoding all or a portion of any of the provided binding molecules, including any of the provided antibodies or antigen-binding fragments or other binding molecules incorporating the same. The provided polynucleotides can be incorporated into constructs, such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) constructs, such as those that can be introduced into cells for expression thereof.217372000540A. CD3 antibody binding domain

[0120] Provided are binding molecules that contain a CD3 antibody binding domain, including full-length antibodies and functional antigen-binding fragments. In some embodiments, the antibodies include antibodies that specifically bind to CD3e, e.g., human CD3e. Exemplary antibodies are described below. In some embodiments, the antibody, e.g., the anti-CD3 antibody, such as a full-length antibody or antigen-binding antibody fragment, contains a heavy chain variable region (VH) sequence and a light chain variable region (VL) sequence as described. In some embodiments, the anti-CD3 antibody is an antigen-binding antibody fragment that is a single chain fragment, such as a single chain Fv (scFv) fragment. In some aspects, the scFv comprises a VH region and a VL region. In some embodiments, the anti-CD3 antibody is an antigen-binding antibody fragment that is an scFv fragment containing a VH region and a VL region. In some embodiments, the scFv fragment is a disulfide-stabilized Fv (dsFv). In some embodiments, the anti-CD3 antibody is an antigenbinding antibody fragment that is a Fab. In some embodiments, the antibodies provided herein bind to human CD3e set forth in SEQ ID NO:82 (UniProt P07766).

[0121] The anti-CD3 binding region of the disclosure agonize, stimulate, activate, and / or otherwise augment CD3-mediated T cell activation. Biological activities of CD3 include, for example, T cell activation and other signaling through interaction between CD3 and the antigen-binding subunits of the T-Cell Receptor (TCR). For example, the anti-CD3 binding domains of the disclosure completely or partially activate T cells via engagement of CD3 (e.g. CD3E) on T cells by partially or completely modulating, e.g., agonizing, stimulating, activating or otherwise augmenting CD3-mediated T cell activation.

[0122] In some embodiments, the anti-CD3 binding region includes one or more copies of an antibody or an antigen-binding fragment thereof selected from the group consisting of a Fab fragment, a F(ab')2 fragment, an Fv fragment, or an a scFv. In some embodiments, the anti-CD3 binding region is monovalent for binding CD3. In some embodiments, the anti-CD3 binding region is a Fab. In some embodiments, the anti-CD3 binding region is a disulfide stabilized Fv fragment.

[0123] Among the provided anti-CD3 antibodies are human antibodies.

[0124] Among the provided antibodies, e.g., antigen-binding fragments, are human antibodies. In some embodiments of a provided human anti-CD3 antibody, e.g., antigenbinding fragments, the human antibody contains a VH region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence217372000540encoded by a germline nucleotide human heavy chain V segment, a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain D segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain J segment; and / or contains a VL region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain V segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain J segment.

[0125] Among the provided antibodies, e.g., antigen-binding fragments, are human antibodies. In some embodiments of a provided human anti- CD3 antibody, e.g., antigenbinding fragments, the human antibody contains a VH region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain V segment, a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain D segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain J segment; and contains a VL region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain V segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain J segment. In some embodiments, the portion of the VH region corresponds to the CDR-H1, the CDR-H2 and / or the CDR-H3. In some embodiments, the portion of the VH region corresponds to the CDR-H1, the CDR-H2 and the CDR-H3. In some embodiments, the portion of the VL region corresponds to the CDR-L1, the CDR-L2 and / or the CDR-L3. In some embodiments, the portion of the VL region corresponds to the CDR-Ll, the CDR-L2 and the CDR-L3.

[0126] Among the provided antibodies are monoclonal antibodies, including monoclonal antibody fragments. The term “monoclonal antibody” as used herein refers to an antibody obtained from or within a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical, except for possible variants containing naturally occurring mutations or arising during production of a monoclonal217372000540antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different epitopes, each monoclonal antibody of a monoclonal antibody preparation is directed against a single epitope on an antigen. The term is not to be construed as requiring production of the antibody by any particular method. A monoclonal antibody may be made by a variety of techniques, including but not limited to generation from a hybridoma, recombinant DNA methods, phage-display and other antibody display methods.

[0127] In some embodiments, the anti- CD3 antibody, e.g., antigen-binding antibody fragment, contains a VH region sequence that contains a heavy chain complementarity determining region 1 (CDR-H1), a CDR-H2 and a CDR-H3 as described and contains a VL region sequence that contains a CDR-L1, a CDR-L2 and / or a CDR-L3 as described. Also among the provided antibodies and fragment thereof are those having sequences at least at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identical to such a sequence, e.g., any of the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3 sequences of the antibodies described herein. Also among the provided antibodies and fragment thereof are those having sequences at least at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identical to such a sequence, e.g., any of the VH and VL sequences, respectively, of the antibodies described herein.

[0128] In some embodiments, provided are anti-CD3 antibodies, including antibody fragments, that have a VH region that comprises a CDR-H1 set forth in SEQ ID NO: 107, a CDR-H2 set forth in SEQ ID NO: 108, and a CDR-H3 set forth in SEQ ID NO: 109; and a VL region that comprises a CDR-L1 set forth in SEQ ID NO: 19, a CDR-L2 set forth in SEQ ID NO: 110, and a CDR-L3 set forth within SEQ ID NO: 6.

[0129] In some embodiments, among provided anti-CD3 antibodies, including antibody fragments, include a VH region that comprises an amino acid sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2X3GIHWVRQAPGKX4LEWVAAIWY DX5SX6X7YYADSVKGRFTISRDNSX8NTLX9LQMNSLRAEDTAVYYCARSNX10DX11L TX12X13YX14X15GX16X17VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is Y or H, X4is G or C; X5is G, A, or S; X6is K, H, or N, X7is K, T, or D; X8is K, E, or S; X9217372000540is Y or D; Xio is Y or F, Xu is I or V, X12 is R or G; X13 is Y or H; X14 is Q or S; X15 is Y or H; Xi6 is I or L; and X17 is N or D; (SEQ ID NO: 156).

[0130] In some embodiments, among provided anti-CD3 antibodies, including antibody fragments, include a VH region that comprises an amino acid sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2X3GIHWVRQAPGKX4LEWVAAIWY DX5SX6X7YYADSVKGRFTISRDNSX8NTLX9LQMNSLRAEDTAVYYCARSNX10DX11L TX12X13YX14X15GX16X17VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is Y or H, X4is G or C; X5is G or A or S; X6is K, H, or N, X7is K, T, or D; X8is K, E, or S; X9 is Y or D; Xio is Y or F, Xu is I or V, X12 is R or G; X13 is Y or H; X14 is Q or S; X15 is Y or H; Xi6 is I or L; and X17 is N or D; (SEQ ID NO: 105).

[0131] In some embodiments, among provided anti-CD3 antibodies, including antibody fragments, include a VL region that comprises an amino acid sequence of the consensus sequence AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASX1LEX2G VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX3SYPRTFGX4GTKVEIK, wherein Xi is S or G, X2is N or S; X3is K or N; and X4is Q or C; (SEQ ID NO: 106).

[0132] In some embodiments, the CDRH1 comprises the sequence set forth in set forth in any one of SEQ ID NOs: 9, 12, 111, or 112, the CDR-H2 comprises the sequence set forth in any one of SEQ ID NOs: 10, 13, 15, 17, or 113-117, and the CDR-H3 comprises the sequence set forth in any one of SEQ ID NOs: 11, 14, 16, 18, 118-123. In some embodiments, the CDR-L1 comprises the sequence set forth in SEQ ID NOs: 19, the CDR-L2 comprises the sequence set forth in any one of SEQ ID NOs: 20, 22, 124, or 125, and the CDR-L3 comprises the sequence set forth in any one of SEQ ID NOs: 21 or 23.

[0133] In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-Hl, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-217372000540H2, and the CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 28, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 42. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 29, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 30, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 31, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 32, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 33, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 34, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 38, and the VL region comprises the217372000540CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 126, and the VL region comprises the CDR-Ll, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 4, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 53, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 54, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 55, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 56, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 57, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 58, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 59, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 60, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 61, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the217372000540CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 62, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 63, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 64, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 65, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 66, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 67, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 68, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 69, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 70, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 71, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 72, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3217372000540contained within SEQ ID NO: 73, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 74, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 75, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 40. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 77. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 78. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 79. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 80. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39. In some embodiments, in the CD3 binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises the CDR-Ll, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39.

[0134] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the217372000540sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 12, 13, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 16, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 17, and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 18, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively. In some embodiments, the VH region217372000540comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 113, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 114, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 115, and 11, respectively, and the VL region comprises the CDR-Ll, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 118, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 18, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 119, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 120, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 16, respectively, and the VL region comprises the CDR-L1, the CDR-L2,217372000540and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 12, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 111, 10, and 11, respectively, and the VL region comprises the CDR-Ll, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 112, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 121, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 122, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 123, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 116, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 117, and 11, respectively, and the VL region comprises the CDR-Ll, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2217372000540and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 18, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 119, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 111, 13, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 113, and 123, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 23, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively. In some embodiments, the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 124, and 21, respectively. In some embodiments, or the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises the CDR-Ll, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19,217372000540125, and 23, respectively. In some embodiments, the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 16, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 12, 13, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 14, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively.

[0135] In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 25, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 26, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence217372000540identity to SEQ ID NO: 28, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 42. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 29, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 30, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41. In some embodiments, in the CD3 binding domain: de VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 32, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 33, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 34, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to ID NO: 40. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%,21737200054086%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 38, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 126, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 4, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 53, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some217372000540embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 54, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 55, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 56, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 57, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 58, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 59, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 60, and the VL region217372000540comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 61, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 62, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 63, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 64, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 65, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 66, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain:217372000540the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 67, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 68, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 69, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 70, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 71, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 72, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 73, and the VL region comprises an amino acid217372000540sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 74, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 75, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 99. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 100. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about21737200054085%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 101. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39. In some embodiments, in the CD3 binding domain: the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 26, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39.

[0136] In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 40, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 26 and 40, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 27 and 41, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 28 and 42, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 29 and 40, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 30 and 41, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 31 and 43, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL217372000540region comprise the sequences set forth in SEQ ID NO: 32 and 40, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 33 and 40, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 34 and 40, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 35 and 40, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 40, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 37 and 40, respectively. In some embodiments, in the CD3 binding domain, or the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 38 and 41, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 126 and 40, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 60 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 61 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 62 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 63 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 64, and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 65 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 66 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 67 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 68 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 69 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 70 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 71 and 39,217372000540respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 72 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 73 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 74 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 75 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 40, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 77, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 81, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 79, respectively. In some embodiments, in the CD3 binding domain. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 80, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 4 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 83 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 54 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 55 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 56 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 57 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 58 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 59 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 27 and 39, respectively. In some embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 39, respectively. In some217372000540embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 26 and 39, respectively.

[0137] The disclosed binding molecules include anti-CD3 antibodies, including antigen binding fragments, comprising specified paratope resides that interact with the human CD3 epsilon. For example, in certain embodiments, the antigen binding domain that specifically binds human CD3 epsilon comprises a heavy chain variable region having at least one amino acid, in the specified position selected from the group consisting of G33, H35, 151, W52, Y53, S99, Y101, 1103, R106, Q109, and Y110 of SEQ ID NO:24 and a light chain variable region having at least one amino acid in the specified position selected from the group consisting of S30, F91, K92, Y94, and R96 of SEQ ID NO:39.

[0138] In another embodiment, the antigen binding domain that specifically binds human CD3 epsilon comprises a heavy chain variable region having amino acids in the specified positions of G33, H35, 151, W52, Y53, S99, Y101, 1103, R106, Q109, and Y110 of SEQ ID NO:24 and a light chain variable region having amino acids in the specified positions of S30, F91, K92, Y94, and R96 of SEQ ID NO:39.

[0139] In some embodiments, provided are anti-CD3 antibodies, including antibody fragments, that have a VH region that comprises a -Hl set forth in SEQ ID NO: 1, a CDR-H2 set forth in SEQ ID NO: 2, and a CDR-H3 set forth in SEQ ID NOG; and a VL region that comprises a CDR-L1 set forth in SEQ ID NO: 19, a CDR-L2 set forth in SEQ ID NO: 5, and a CDR-L3 set forth within SEQ ID NO: 6.

[0140] In some embodiments, among provided anti-CD3 antibodies, including antibody fragments, include a VH region that comprises a sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD X4SKX5YYADSVKGRFTISRDNSX6NTLX7LQMNSLRAEDTAVYYCARSNYDILTX8X9 YX10X11GX12X13VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is G or C; X4is G or A; X5is K, T, or D; X6is K, E, or S; X7is Y or D; X8is R or G; X9is Y or H; X10 is Q or S; Xu is Y or H; X12 is I or L; and X13 is N or D; (SEQ ID NOG).

[0141] In some embodiments, among provided anti-CD3 antibodies, including antibody fragments, include a VL region that comprises a sequence of the consensus sequence AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLEXiGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX2SYPRTFGX3GTKVEIK, wherein Xi is N or S; X2is K or N; X3is Q or C; (SEQ ID NOG).

[0142] In some embodiments, provided anti-CD3 antibodies, including antibody fragments, comprises a VH region comprising a CDR-H1, a CDR-H2 and a CDR-H3 present217372000540in (or contained in) a VH sequence set forth in any one of SEQ ID NOs: 24-38, and a VL region comprising CDR-L1, a CDR-L2, and a CDR-L3 present in (or contained in) a VL sequence set forth in any one of SEQ ID NO:39-43.

[0143] In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 according to Kabat numbering. In some embodiments, the VL region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to Kabat numbering.

[0144] In some embodiments, the CDRH1 comprises the amino acid sequence set forth in set forth in any one of SEQ ID NOs: 9 or 12, the CDR-H2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 10, 13, 15, or 17, and the CDR-H3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 11, 14, 16, or 18. In some embodiments, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NOs: 19, the CDR-L2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 20 or 22, and the CDR-L3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 21 or 23.

[0145] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 39, respectively. In some embodiments, the CD3 binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 128. In some embodiments, the binding domain comprises an the amino acid sequence of SEQ ID NO: 128.

[0146] In some embodiments, among provided binding molecules provided herein are binding molecules in which an antibody, including antigen binding fragment, disclosed217372000540herein may comprise one or more amino acid substitutions, insertions and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains as compared to a reference human antibody or compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to the reference sequence or to germline sequences available from, for example, public antibody sequence databases.

[0147] In some embodiments, the binding molecules provided herein include antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and / or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as "germline mutations"). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and / or CDR residues within the VH and / or VL domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8amino acids of FR4, or only the mutated residues found within CDR1, CDR2or CDR3. In other embodiments, one or more of the framework and / or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies of the present invention may contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case217372000540may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present invention.

[0148] In some embodiments, the binding molecules provided herein include antibodies, and antigen-binding fragments thereof, comprising variants in which the framework and / or CDR regions are mutated with one or more conservative substitutions. For example, the present invention includes antibodies and antibody fragments having framework and / or CDR regions amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the framework and / or CDR regions amino acid sequences set forth in the tables herein.

[0149] In some embodiments, the anti-CD3 antibody can be chosen as having a particular or desired binding affinity. In some embodiments, the anti-CD3 antibody has a CD3 dissociation constant (Kd) of < 1 pM, < 100 nM, <10 nM, < 1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10’8M or less, e.g., from 10’8M to 10’13M, e.g., from 10’9M to 1013M). In some embodiments, the provided binding molecules, including bispecific antibodies, incorporate anti-CD3 antibodies that exhibit a medium binding affinity for binding to CD3. In some embodiments, an anti-CD3 antibody exhibits a binding affinity (Kd) that is greater than 5 nM. In some embodiments, an anti-CD3 antibody incorporated in bispecific antibodies herein exhibits a binding affinity (Kd) that is greater than 10 nM. In some embodiments, the Kd of an anti-CD3 antibody is at or about 5 nM, 7.5 nM, 10 nM, 15 nM, 20 nM, 25 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, or any value between any of the foregoing. In some embodiments, the Kd of an anti-CD3 antibody is between 10 nM and 70 nM.

[0150] In a particular embodiments, among provided antibodies are antibodies, including antigen binding fragments, that comprise one or more amino acid substitution in the framework and / or CDR region relative to the antibody designated CD3-1, for example, an anti-CD3 antibody comprising in which the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 39, respectively.

[0151] In some embodiments, the VH region comprises a CDR-H1 set forth in SEQ ID NO: 1, a CDR-H2 set forth in SEQ ID NO: 85, and a CDR-H3 set forth in SEQ ID NO:3; and the VL region comprises a CDR-L1 set forth in SEQ ID NO: 19, a CDR-L2 set forth in SEQ ID NO: 22, and a CDR-L3 set forth within SEQ ID NO: 6.

[0152] In some embodiments, among provided anti-CD3 antibodies, including antibody fragments, include a VH region that comprises a sequence of the consensus sequenceQVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD217372000540ASKX4YYADSVKGRFTISRDNSX5NTLYLQMNSLRAEDTAVYYCARSNYDILTX6X7Y XsXgGXioXnVWGQGTTVTVSS, wherein Xi=R or G or E; X2=R or N; X3=G or C; X4=K or T or D; X5=K or E or S; X6=R or G; X7=Y or H; X8=Q or S; X9=Y or H; Xio= I or L; and Xn=N or D (SEQ ID NO: 83).

[0153] In some embodiments, among provided anti-CD3 antibodies, including antibody fragments, include a light chain variable (VL) region that comprises a sequence of the consensus sequence AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX1SYPRTFGX2GTKVEIK (SEQ ID NO:84), wherein Xi=K or N and X2=Q or C.

[0154] In some embodiments, the VH region comprises one or more amino acid residues selected from the group consisting of: an asparagine (N) at position 31 , an alanine (A) at position 55, a tyrosine (Y) at position 80, a glycine (G) at position 106, a histidine (H) at position 107, a serine (S) at position 109, a histidine (H) at position 110, a leucine (E) at position 112, and an aspartic acid (D) at position 113 or any combination thereof, wherein the numbering is relative to SEQ ID NO: 24. In some embodiments, the VL region comprises one or more amino acid residues selected from the group consisting of: a serine (S) at position 56 and an asparagine (N) at position 92, a cysteine (C) at position 100, and an asparagine (N) at position 108, or any combination thereof, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region comprises one or more amino acid residues selected from the group consisting of: an asparagine (N) at position 31 , an alanine (A) at position 55, a tyrosine (Y) at position 80, a glycine (G) at position 106, a histidine (H) at position 107, a serine (S) at position 109, a histidine (H) at position 110, a leucine (L) at position 112, and an aspartic acid (D) at position 113 or any combination thereof, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises one or more amino acid residues selected from the group consisting of: a serine (S) at position 56 and an asparagine (N) at position 92, or any combination thereof, wherein the numbering is relative to SEQ ID NO: 39. In some of any such embodiments, the Kd of an anti-CD3 antibody is between 10 nM and 70 nM, such as 10 nM, 15 nM, 20 nM, 25 nM, 30 nM, 40 nM, 50 nM, 60 nM, or 70 nM, or any value between any of the foregoing.

[0155] In some embodiments, the VH region comprises amino acid residues alanine (A) at position 55 and tyrosine (Y) at position 80, wherein the numbering is relative to SEQ ID NO: 24.217372000540

[0156] In some embodiments, the VH region comprises amino acid residues asparagine (N) at position 31, alanine (A) at position 55, and tyrosine (Y) at position 80, wherein the numbering is relative to SEQ ID NO: 24. In some embodiments, the VH region comprises amino acid residues alanine (A) at position 55, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 24. In some embodiments, the VH region comprises amino acid residues alanine (A) at position 55, tyrosine (Y) at position 80, serine (S) at position 109, and histidine (H) at position 110, wherein the numbering is relative to SEQ ID NO: 24. In some embodiments, the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO:39. In some embodiments, the VL region comprises serine (S) at position 56 and asparagine (N) at position 92, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region comprises amino acid residues asparagine (N) at position 31, alanine (A) at position 55, and tyrosine (Y) at position 80, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO:39. In some embodiments, the VH region comprises amino acid residues alanine (A) at position 55, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO:39. In some embodiments, the VH region comprises amino acid residues alanine (A) at position 55, tyrosine (Y) at position 80, serine (S) at position 109, and histidine (H) at position 110, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56 and asparagine (N) at position 92, wherein the numbering is relative to SEQ ID NO: 39. In some of any such embodiments, the Kd of an anti-CD3 antibody is between 10 nM and 70 nM, such as 10 nM, 15 nM, 20 nM, 25 nM, 30 nM, 40 nM, 50 nM, 60 nM, or 70 nM, or any value between any of the foregoing. In some of any such embodiments, the anti-CD3 antibody has a Kd of 5 to 75 nM to CD3. In some of any such embodiments, the anti-CD3 antibody has a Kd of 10 to 70 nM to CD3.

[0157] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 12, 13 and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 21, respectively. In some embodiments, the VH region comprises an amino acid sequence that217372000540has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 25, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, the VH region comprises amino acid residues asparagine (N) at position 31, alanine (A) at position 55, and tyrosine (Y) at position 80, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO:39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 25 and 40, respectively. In some embodiments, the binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 129. In some embodiments, the binding domain comprises an the amino acid sequence of SEQ ID NO: 129.

[0158] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13 and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 21, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 26, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, the VH region comprises amino acid residues alanine (A) at position 55, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO:39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 26 and 40, respectively.

[0159] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41. In some embodiments, the VH217372000540region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13 and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 23, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41. In some embodiments, the VH region comprises amino acid residues alanine (A) at position 55, tyrosine (Y) at position 80, serine (S) at position 109, and histidine (H) at position 110, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56 and asparagine (N) at position 108, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 27 and 41, respectively.

[0160] In some embodiments, the provided anti-CD3 antibodies or antigen-binding fragments thereof low polyreactivity. As used herein, an antibody or antigen-binding fragment thereof that exhibits “low polyreactivity” exhibits low non-specific binding to extracellular matrix proteins. Thus, in some embodiments, the provided anti-CD3 antibodies and antigen-binding fragments thereof exhibit low polyreactivity to extracellular matrix (ECM) proteins. This is advantageous because low polyreactivity with ECM proteins can reduce off-target effects caused by the antibody binding to ECM proteins, and can reduce or avoid the negative effects that polyreactivity can have on pharmacokinetics and bioavailability of the antibody.

[0161] Accordingly, in some embodiments, the anti-CD3 antibody or antigen-binding fragment thereof exhibits low non-specific binding to extracellular matrix proteins, such as by having an extracellular matrix (ECM) score of less than 14, less than 13, less than 12, less than 11, or less than 10. Low polyreactivity is advantageous because it can, e.g., reduce off-target effects caused by the antibody binding to extracellular matrix proteins, for instance; and it can also reduce or avoid the negative effects that polyreactivity can have on pharmacokinetics and bioavailability of the therapeutic antibody. Polyreactivity can be assessed by, for instance, reference to an ECM score that is calculated based on an ECM ELISA assay, where the ECM score is calculated by dividing the absorbance value of an ECM-coated sample well containing the antibody or antigen-binding fragment thereof by the absorbance of an ECM-coated sample well that does not contain the antibody or antigen-217372000540binding fragment thereof. In some embodiments, an ECM score of 12 at a concentration of 1 |jM antibody or antigen-binding fragment thereof is used to determine whether an antibody or antigen-binding fragment thereof has a high or low ECM score, with a high ECM score being at or higher than 12, and a low ECM score being less than 12. In some embodiments, the anti-CD3 antibody or antigen-binding fragment thereof has an ECM score of less than 14, less than 13, less than 12, less than 11, or less than 10. In some embodiments, the anti-CD3 antibody or antigen-binding fragment thereof has an ECM score of less than 12.

[0162] In some embodiments, the VH region comprises one or more amino acid residues selected from glycine (G) at position 16, a glutamic acid (E) at position 16, a threonine (T) at position 58, an aspartic acid (D) at position 58, a glutamic acid (E) at position 76, a serine (S) at position 76, wherein the numbering is relative to SEQ ID NO: 24. In some embodiments, the VH region comprises glycine (G) at position 16, wherein the numbering is relative to SEQ ID NO: 24. In some embodiments, the VH region comprises a threonine (T) at position 58, wherein the numbering is relative to SEQ ID NO: 24. In some embodiments, the VH region comprises glycine (G) at position 16 and a threonine (T) at position 58, wherein the numbering is relative to SEQ ID NO: 24. In some of any such embodiments, the anti-CD3 antibody or antigen-binding fragment thereof has a low polyreactivity with an ECM score of less than 14, less than 13, less than 12, less than 11, or less than 10. In particular embodiments, the ECM score is less than 12.

[0163] In some embodiments, any of the provided antibodies or antigen-binding fragments are single chain variable fragments (scFv). In some embodiments, the scFv is a disulfide-stablized scFv (dsFv) wherein the VH includes a first engineered cysteine residue and the VL includes a second engineered cysteine residue and wherein the first engineered cysteine residue and the second engineered cysteine residue form a disulfide bond. In some embodiments, the first engineered cysteine residue is at position 44 (e.g., G44C amino acid substitution) in the VH, wherein the numbering is relative to SEQ ID NO: 24. In some embodiments, the second engineered cysteine residue is at position 100 (e.g., Q100C amino acid substitution) in the VL, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the first engineered cysteine residue is at position 44 (e.g, G44C amino acid substitution) in the VH (wherein the numbering is relative to SEQ ID NO: 24) and the second engineered cysteine residue is at position 100 (e.g., Q100C amino acid substitution) in the VL (wherein the numbering is relative to SEQ ID NO: 39).

[0164] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 28, and the VL region comprises the CDR-L1, the217372000540CDR-L2, and the CDR-L3 contained within SEQ ID NO: 42. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15 and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 21, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 28, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 42. In some embodiments, the VH comprises glycine (G) at position 16, cysteine (C) at position 44, a threonine (T) at position 58, alanine (A) at position 55, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113 , wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56 and cysteine (C) at position 100, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 28 and 42, respectively. In some embodiments, the CD3 binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 130. In some embodiments, the CD3 binding domain comprises an amino acid sequence of SEQ ID NO: 130.

[0165] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 29, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15 and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 21, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 29, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, the VH comprises amino acid residues glycine (G) at position 16, alanine (A) at position 55, threonine (T) at position 58, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO:21737200054024, and the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 29 and 40, respectively.

[0166] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 30, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15 and 16, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 23, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 30, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41. In some embodiments, the VH comprises amino acid residues glycine (G) at position 16, alanine (A) at position 55, threonine (T) at position 58, tyrosine (Y) at position 80, serine (S) at position 109, and histidine (H) at position 110, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56 and asparagine (N) at position 92, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 29 and 40, respectively.

[0167] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 31, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15 and 16, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 23, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43. In some embodiments, the VH comprises amino acid residues glycine (G) at position 16, cysteine (C) at position 44, alanine (A) at position 55, threonine (T) at position 58, tyrosine (Y) at position 80, serine (S) at position 109, and histidine (H) at position 110, wherein the numbering is217372000540relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56, asparagine (N) at position 92 and cysteine (C) at position 100, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 31 and 43, respectively. In some embodiments, the CD3 binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 131. In some embodiments, the CD3 binding domain comprises the amino acid sequence of SEQ ID NO: 131.

[0168] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 32, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13 and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 21, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 32, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, the VH comprises amino acid residues glycine (G) at position 16, alanine (A) at position 55, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 32 and 40, respectively.

[0169] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13 and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 21, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 26, and the VL region comprises an217372000540amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, the VH comprises amino acid residues a glutamic acid (E) at position 16, alanine (A) at position 55, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 26 and 40, respectively.

[0170] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 33, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 17 and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 21, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 33, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, the VH comprises amino acid residues a glutamic acid (E) at position 16, alanine (A) at position 55, aspartic acid (D) at position 58, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 33 and 40, respectively.

[0171] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 34, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15 and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 21, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 34, and the VL region comprises an217372000540amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, the VH comprises amino acid residues a glycine (G) at position 16, alanine (A) at position 55, threonine (T) at position 58, serine (S) at position 76, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 34 and 40, respectively.

[0172] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 17 and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 21, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, the VH comprises amino acid residues a glutamic acid (E) at position 16, alanine (A) at position 55, aspartic acid (D) at position 58, serine (S) at position 76, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 35 and 40, respectively.

[0173] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13 and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 21, respectively. In some embodiments, the VH region comprises an amino acid sequence that217372000540has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, the VH comprises amino acid residues a glycine (G) at position 16, alanine (A) at position 55, serine (S) at position 76, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 40, respectively.

[0174] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13 and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 21, respectively. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40. In some embodiments, the VH comprises amino acid residues a glutamic acid (E) at position 16, alanine (A) at position 55, glutamic acid (E) at position 76, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 37 and 40, respectively.

[0175] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15 and 18, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22 and 23, respectively. In some embodiments, the VH region comprises an amino acid sequence that217372000540has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 38, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41. In some embodiments, the VH comprises amino acid residues a glycine (G) at position 16, alanine (A) at position 55, threonine (T) at position 58, tyrosine (Y) at position 80, glycine (G) at position 106, and histidine (H) at position 107, wherein the numbering is relative to SEQ ID NO: 24, and the VL region comprises serine (S) at position 56 and asparagine (N) at position 92, wherein the numbering is relative to SEQ ID NO: 39. In some embodiments, the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 38 and 41, respectively.

[0176] In some embodiments, a provided binding molecule is an antibody or an antigenbinding fragment containing any of the above VH and VL regions, and their combinations, described above. In some embodiments, the antibody or antigen-binding fragment further includes human immunoglobulin constant regions. In some embodiments, the antibody or antigen-binding fragment is an antigen-binding fragment. In some embodiments, the antigenbinding fragment format retains CD3 binding conferred by the VH and VL regions. In some embodiments, the antigen-binding fragment may be an Fv, scFv, Fab, Fab', F(ab')2, or other antigen-binding fragment of antibodies. In some embodiments, the antibody or antigenbinding fragment is a full-length antibody that comprises human immunoglobulin constant regions, including an Fc region.

[0177] Antigen-binding fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells. In some embodiments, the antibodies are recombinantly-produced fragments, such as fragments comprising arrangements that do not occur naturally, such as those with two or more antibody regions or chains joined by synthetic linkers, e.g., peptide linkers, and / or that may not be produced by enzyme digestion of a naturally-occurring intact antibody.

[0178] In some embodiments, the antibody or antigen-binding fragment is an scFv containing any of the above VH and VL regions. In some embodiments, the scFv includes a linker joining the two antibody VH and VL region. The linker typically is a peptide linker, e.g., a flexible and / or soluble peptide linker, such as one rich in glycine and serine. In some aspects, the linker rich in glycine and serine (and / or threonine) includes at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% glycine, serine, and / or threonine amino acid(s). In some embodiments, the linker includes at least at or about 50%, 55%, 60%,21737200054070%, or 75%, glycine, serine, and / or threonine. In some embodiments, the linker is comprised substantially entirely of glycine, serine, and / or threonine. The linkers generally are between about 5 and about 50 amino acids in length, typically between at or about 10 and at or about 30, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and in some examples between 10 and 25 amino acids in length. Exemplary linkers include linkers having various numbers of repeats of the sequence GGGGS (4GS; SEQ ID NO: 94) or GGGS (3GS; SEQ ID NO: 97), such as between 2, 3, 4 and 5 repeats of such a sequence. Exemplary linkers include those having the sequence set forth in SEQ ID NO: 96 (GGGGSGGGGSGGGGS). Exemplary linkers further include those having the sequence set forth in SEQ ID NO: 98 (GSTSGSGKPGSGEGSTKG). Exemplary linkers further include those having or consisting of the sequence set forth in SEQ ID NO: 99 (SRGGGGSGGGGSGGGGSLEMA). An exemplary linker includes those having or consisting of the sequence set forth in SEQ ID NO: 100 (GSRGGGGSGGGGSGGGGSLEMA). In some embodiments, the VH region may be amino terminal to the VL region. In some embodiments, the VH region may be carboxy terminal to the VL region. In particular embodiments, the fragment, e.g., scFv, may include a VH region or portion thereof, followed by the linker, followed by a VL region or portion thereof. In other embodiments, the fragment, e.g., the scFv, may include the VL region or portion thereof, followed by the linker, followed by the VH region or portion thereof.

[0179] In some embodiments, the scFv is a disulfide-stabilized Fv (ds-scFv) in which the VH and VL contain a first and second engineered cysteine residue, respectively, that form a disulfide bond. In some embodiments, the first engineered cysteine residue is at position 44 (e.g, G44C amino acid substitution) in the VH, wherein the numbering is relative to SEQ ID NO: 24, and the second engineered cysteine residue is at position 100 (e.g., G100C amino acid substitution) in the VL, wherein the numbering is relative to SEQ ID NO: 39.

[0180] In some embodiments, the antibody or antigen-binding fragment is an scFv comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 128. In some embodiments, the scFv comprises the amino acid sequence of SEQ ID NO: 128. In some embodiments, the antibody or antigen-binding fragment is an scFv comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 129. In some embodiments, the scFv comprises the amino acid sequence of SEQ ID NO: 129. In some embodiments, the antibody217372000540or antigen-binding fragment is an scFv comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 130. In some embodiments, the scFv comprises the amino acid sequence of SEQ ID NO: 130. In some embodiments, the antibody or antigen-binding fragment is an scFv comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 131. In some embodiments, the scFv comprises the amino acid sequence of SEQ ID NO: 131.

[0181] In some such embodiments, the antibody is a full-length antibody that also contains a heavy chain and light chain constant region. In some embodiments, the antibody comprises a constant region from an IgGl or IgG2. In some embodiments, the constant region is a human IgGl heavy chain constant region. In some embodiments, the antibody includes at least a portion of a hinge region or a variant thereof. In some embodiments, the antibody includes a CH2 and / or CH3 domain, such as an Fc region. In some embodiments, the Fc region is an Fc region of a human IgG, such as an IgGl or IgG4. In some embodiments, the heavy chain constant portion is derived from an IgGl immunoglobulin constant chain. In some embodiments, the light chain CE is from a kappa or lambda light chain sequence.

[0182] In some embodiments, the constant light chain is a (lambda) light chain. In some embodiments, the constant light (CL) is set forth by the sequence in SEQ ID NO: 103 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 103.

[0183] In some embodiments, the constant light chain is a K (kappa) light chain. In some embodiments, the CL is set forth by the sequence in SEQ ID NO: 52 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:52.

[0184] In some embodiments, the constant light chain is a K light chain. In some embodiments, the CL is set forth by the sequence in SEQ ID NO: 104 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 104.

[0185] In some embodiments, the antibody or antigen-binding fragment is an antigenbinding fragment that further comprises at least a portion of an immunoglobulin constant region of the heavy chain and at least a portion of an immunoglobulin constant region of the217372000540light chain. In some embodiments, the CD3 binding domain is an anti-CD3 antibody that is a Fab containing any of the above VH and VL regions. In some embodiments, the Fab contains a heavy chain comprising any one of the above VH regions and an immunoglobulin constant heavy chain domain 1 (CHI domain) and a light chain comprising any one of the above VL regions and an immunoglobulin CL.

[0186] In some embodiments, the CHI is from an IgGl antibody. In some embodiments, the CHI is set forth by the sequence in SEQ ID NO: 101 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO: 101. In some embodiments, the CHI is set forth by the sequence in SEQ ID NO: 102 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 102. In some embodiments, the CHI is set forth by the sequence in SEQ ID NO: 50 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:50.

[0187] In some embodiments, the CHI is from an IgG2 antibody, n some embodiments, the CHI is set forth by the sequence in SEQ ID NO: 51 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:51.

[0188] In some embodiments, the CL is a kappa constant domain. In some embodiments, the CL is set forth by the sequence in SEQ ID NO: 52 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:52. In some embodiments, the CL is set forth by the sequence in SEQ ID NO: 104 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 104.

[0189] In some embodiments, the CL is a lambda constant domain. In some embodiments, the CL is set forth by the sequence in SEQ ID NO: 103 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 103.

[0190] In some embodiments, the CD3 binding domain is an anti-CD3 antibody that is a Fab composed of a heavy chain comprising any one of the above VH regions and an CHI domain set forth in SEQ ID NO: 50, and a light chain comprising any one of the above VL regions and an immunoglobulin CL set forth in SEQ ID NO: 52. In some embodiments, the CD3 binding domain is a Fab comprising a heavy chain comprising a VH set forth by the sequence of SEQ ID NO:29 and a CHI comprising the sequence set forth in SEQ ID NO:50,217372000540and a light chain comprising a VL set forth by the sequence of SEQ ID NO: 76 and a CL comprising the sequence set forth in SEQ ID NO: 52. In some embodiments, the CD3 binding domain is a Fab comprising a heavy chain comprising a VH set forth by the sequence of SEQ ID NO:30 and a CHI comprising the sequence set forth in SEQ ID NO:50, and a light chain comprising a VL set forth by the sequence of SEQ ID NO: 81 and a CL comprising the sequence set forth in SEQ ID NO: 52.

[0191] In some such embodiments, the antibody is a full-length antibody that also contains a heavy chain and light chain constant region. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof, is a human IgG. In some embodiments, the antibody comprises a constant region from an IgGl or IgG2. In some embodiments, the constant region is a human IgGl heavy chain constant region. In some embodiments, the antibody includes at least a portion of a hinge region or a variant thereof. In some embodiments, the antibody includes a CH2 and / or CH3 domain, such as an Fc region. In some embodiments, the Fc region is an Fc region of a human IgG, such as an IgGl or IgG4. In some embodiments, the heavy chain constant portion is derived from an IgGl immunoglobulin constant chain. In some embodiments, the light chain CL is from a kappa or lambda light chain sequence.

[0192] In full-length antibody embodiments, the antibody comprises two heavy chains and two light chains (H2L2), wherein each heavy chain comprises a VH region and a heavychain constant region and each light chain comprises a VL region and a light-chain constant region, and the heavy chain may include an Fc region comprising at least part of the hinge, CH2, and CH3 domains. Among the provided antibodies are full-length antibodies containing a heavy chain with any one of the VH regions provided herein combined with a human heavy chain constant region; and a light chain with any one of the VL regions provided herein combined with a human light chain constant region.

[0193] In some embodiments, the constant region of the heavy chain is a human IgGl heavy chain constant region. In some embodiments, the heavy chain constant region is set forth in SEQ ID NO: 86 or a sequence that has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 86. In some embodiments, the heavy chain constant region is set forth in SEQ ID NO: 86. In some embodiments, the heavy chain constant region is set forth in SEQ ID NO: 87 or a sequence that has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 87. In some embodiments, the heavy chain constant region is set forth in SEQ ID NO: 87.217372000540

[0194] In some embodiments, the constant light chain is a (lambda) light chain. In some embodiments, the constant light (CL) is set forth by the sequence in SEQ ID NO: 103 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 103.

[0195] In some embodiments, the constant light chain is a K (kappa) light chain. In some embodiments, the constant light chain (CL) is set forth by the sequence in SEQ ID NO: 52 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:52.

[0196] In some embodiments, the constant light chain is a K (kappa) light chain. In some embodiments, the constant light chain (CL) is set forth by the sequence in SEQ ID NO: 104 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 104.

[0197] In some embodiments, the heavy chain constant region is mutated or modified relative to a wild-type immunoglobulin constant region (e.g., a human IgG constant region) to provide a modified (or variant) Fc region, when an Fc region or portion thereof is present. In some embodiments, the modified constant region comprises a modified Fc region (e.g., a human IgGl, IgG2, IgG3, or IgG4 Fc region) comprising one or more amino acid modifications (e.g., substitutions and / or deletions) at one or more amino acid positions. In some embodiments, the Fc region comprises a hinge region, CH2, and CH3.

[0198] In some cases, the mutations include one or more amino acid substitutions in the heavy chain constant region, such as the heavy chain constant region of IgGl, to reduce effector activity of the heavy chain constant region. In some embodiments, the Fc region is mutated or modified to reduce or eliminate one or more Fc effector functions (e.g., Fey receptor binding and / or Clq binding). In some embodiments, such mutation or modification substantially retains FcRn binding. Exemplary mutations in an Fc that can be included to reduce or eliminate one or more Fc effector functions, optionally while retaining FcRn binding are described in Section II.B.2. Any other mutation (e.g., substitution) described in Section II.B.2 may also be included an a Fc constant region sequence of a provided antibody.

[0199] In some embodiments, a provided antibody or antigen-binding fragment is a full length antibody that is capable of forming a dimer via Fc-mediated association. In some embodiments, the Fc region comprises a first Fc-containing polypeptide chain and a second Fc-containing polypeptide chain that associate to form a homodimer comprising two identical Fc-containing polypeptide chains. In some embodiments, dimerization is mediated by interactions within one or more constant-region domains of the Fc region (e.g., hinge, CH2,217372000540and / or CH3) and, where present, inter-chain disulfide bonds in the hinge. In some embodiments, the Fc region is formed by Fc domains that are mutated or modified to promote heterodimerization in which different polypeptides can be dimerized to yield a heterodimer. Thus, in some embodiments, the dimer is a heterodimer in which two polypeptide chains of the antibody are different. Exemplary modifications to promote heterodimerization are known, including any as described below in Section II.B.2.

[0200] In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 133; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 134. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 135; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 137; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 138; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 139. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,21737200054094%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 140; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 141. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 142; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 143; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 139. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 144; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 145. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 146; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 147; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%,21737200054090%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 148; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 149; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 150; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 151; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 152; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof217372000540comprises: (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 153; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 136.

[0201] In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 133; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 134. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: heavy chain comprising the amino acid sequence of SEQ ID NO: 135; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 137; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 138; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 139. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 140; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 141. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 142; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 143; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 139. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 144; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 145. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 146; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 147; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody,217372000540or an antigen binding fragment thereof comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 148; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 149; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 150; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 151; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 152; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 136. In some embodiments, the anti-CD3 antibody, or an antigen binding fragment thereof comprises: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 153; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 136.

[0202] Also provided are methods of making the CD3 binding molecules, including anti-CD3 antibodies (including antigen-binding fragments) or a binding molecule incorporating such antibodies or fragments. For recombinant production of the binding molecule, such as an anti-CD3 antibody, a polynucleotide sequence or a polynucleotide encoding an antibody, e.g., as described above, may be isolated and inserted into one or more vectors for further cloning and / or expression in a host cell. Such polynucleotide sequences may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody). In some embodiments, a method of making the CD3 binding molecules, such as anti-CD3 antibody, is provided, wherein the method comprises culturing a host cell comprising a polynucleotide sequence encoding the binding molecule, as provided above, under conditions suitable for expression of the binding molecule, and optionally recovering the binding molecule from the host cell (or host cell culture medium).

[0203] Exemplary eukaryotic cells that may be used to express polypeptides include, but are not limited to, COS cells, including COS 7 cells; 293 cells, including 293-6E cells; CHO cells, including CHO-S, DG44. Lecl3 CHO cells, and FUT8 CHO cells; PER.C6® cells; and NSO cells. In some embodiments, the antibody heavy chains and / or light chains (e.g., VH217372000540region and / or VL region) may be expressed in yeast. See, e.g., U.S. Publication No. US 2006 / 0270045 Al. In some embodiments, a particular eukaryotic host cell is selected based on its ability to make desired post-translational modifications to the heavy chains and / or light chains (e.g., VH region and / or VL region). For example, in some embodiments, CHO cells produce polypeptides that have a higher level of sialylation than the same polypeptide produced in 293 cells.

[0204] In some embodiments, the antibody or antigen-binding fragment provided herein is produced in a cell-free system. Exemplary cell-free systems are described, e.g., in Sitaraman et al., Methods Mol. Biol. 498: 229-44 (2009); Spirin, Trends Biotechnol. 22: 538-45 (2004); Endo et al., Biotechnol. Adv. 21: 695-713 (2003).

[0205] In some of any of such embodiments, the anti-CD3 antibody or antigen-binding fragment thereof comprises at least one post-translational modification of the amino acid sequence. Post-translational modifications can include, e.g., glycosylation, phosphorylation, citrullination, isomerization, ubiquitination, acetylation, hydroxylation, methylation, AMPylation, prenylation, deamidation, eliminylation, carbamylation and carbamoylation. In some embodiments, the post-translational modification is the modification of an amino acid side chain, such as conversion of an N-terminal amino acid e.g., glutamate or glutamine) to pyroglutamate. In some such embodiments, this modification occurs at the N-terminus of the heavy chain. In some embodiments, the post-translational modification includes a post-translational modification of a heavy chain N-terminal glutamine (Q) to a pyroglutamate. In some embodiments, in a composition of an antibody or antigen-binding fragment thereof as disclosed herein, such a post-translational modification to pyroglutamate (e.g., at the N-terminus of the heavy chain) is a dominant post-translational modification; in some such embodiments, the antibody or antigen binding fragment thereof in which an N-terminal pyroglutamate is present represents greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, or greater than 95% (w / w) of the antibody or antigen binding fragment thereof in the composition.

[0206] In some embodiments, the post-translational modification is the cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. For instance, an antibody produced by expression of a specific nucleic acid molecule encoding a full-length heavy chain (e.g., by expression in a host cell) may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case where the final two C-terminal amino acids of the heavy chain are glycine and lysine, respectively. Therefore, the C-terminal lysine, or the C-terminal glycine and lysine, of the Fc217372000540region may or may not be present. Thus, an anti-CD3 antibody may include a heavy chain constant domain with both a C-terminal glycine and lysine, without the C-terminal lysine, or without both the C-terminal glycine and lysine. In some embodiments, in a composition of an antibody or antigen-binding fragment thereof as disclosed herein, glycine cleavage is not a dominant post-translational modification; in some such embodiments, the antibody or antigen binding fragment thereof in which the C-terminal lysine is cleaved from the heavy chain constant domain represents less than 10%, less than 5%, or less than 4% (w / w) of the antibody or antigen binding fragment thereof in the composition.B. Bispecific Binding molecules

[0207] In some embodiments, provided herein are multispecific antigen-binding molecules that include any of the CD3 binding domains described herein. In some embodiments, the multispecific antigen-binding molecules are bispecific antigen-binding molecules.

[0208] In some embodiments, any of the exemplary binding molecules can include an anti-CD3 antibody or antigen binding antibody fragment comprised in a multispecific antibody composed of at least one anti-CD3 antibody that is formatted with at least one additional antibody directed against a second target antigen. In some embodiments, the multispecific antibody is a bispecific T cell engager specific for CD3 and the second target antigen. In some embodiments, the multspecific antibody is composed of at least one anti-CD3 antibody or antigen-binding fragment (e.g., anti-CD3 scFv or Fab) and an antibody or antigen-binding fragment (e.g., Fab or scFv) directed against a second antigen. In any of such embodiments, the binding molecule is a bispecific antigen binding molecule, such as a bispecific antibody, that has binding specificity for both CD3 and the second antigen.

[0209] The term "bispecific antibody" as used herein means a monoclonal antibody that has binding specificity for two different epitopes. Bispecific antibodies can be prepared as full-length antibodies or antibody fragments.

[0210] In some embodiments, the anti-CD3 antibody activates T cells via engagement of CD3, such as CD3e, on the T cells. The anti-CD3 antibody exhibits activity to agonize, stimulate, activate, and / or otherwise augment CD3-mediated T cell activation. Biological activities of CD3 include, for example, T cell activation and other signaling through interaction between CD3 and the antigen-binding subunits of the T-Cell Receptor (TCR). Any of a variety of methods are known for measuring T cell activation. In some embodiments, T cell activation can be assessed by determining the ability of a provided217372000540bispecific antibody to stimulate cytokine production, proliferation or cytotoxic activity in T cell cultures. In some embodiments, the activity is present in co-cultures of T cells with antigen-expressing target cells but not present in the absence of antigen-expressing cells. In some embodiments, the bispecific antibodies elicit potent T cell activation or T cell killing when also engaged by or bound to the target (second) antigen, such as target antigenexpressing target cells (e.g., target antigen-expresssing tumor cells).

[0211] In some embodiments, the binding molecule containing a CD3 binding domain provides for a T cell engaging therapy. The T cell-engaging therapy is a bispecific antibody containing at least one antigen-binding domain binding to an activating component of the T cell such as CD3 and at least one antigen-binding domain binding to a second antigen that is present on a target cell desired to be targeted. In some embodiments, the simultaneous or near simultaneous binding of such an antibody to both of its targets can result in a temporary interaction between the target cell and T cell, thereby resulting in activation, e.g. cytotoxic activity, of the T cell and subsequent lysis of the target cell.

[0212] The provided bispecific antibodies provide a targeted antibody therapy for delivering cytotoxic T cells specifically to the target cells expressing the second antigen, such as target-expressing cancer cells. Hence, in some aspects the provided bispecific antibodies may also be called TCEs. In particular embodiments, the provided bispecific antibodies can be used in therapeutic settings in which specific targeting and T cell-mediated killing of cells that express the second antigen is desired.

[0213] In some embodiments, biological activity or functional activity of a provided bispecific antibody, such as cytotoxic activity, can be measured using any of a number of known methods. The activity can be assessed or determined either in vitro or in vivo. In some embodiments, activity can be assessed once the bispecific antibody is administered to the subject e.g., human). Parameters to assess include specific binding of the bispecific antibody to a T cell (e.g., natural T cell) or target antigen-expressing cell, e.g., in vivo, e.g., by imaging, or ex vivo, e.g., by ELISA or flow cytometry. In certain embodiments, the ability of the bispecific antibody to destroy target cells can be measured using any suitable known methods, such as cytotoxicity assays described in, for example, Kochenderfer et al., J. Immunotherapy, 32(7): 689-702 (2009), and Herman et al. J. Immunological Methods, 285(1): 25-40 (2004). In certain embodiments, the biological activity of the bispecific antibody also can be measured by assaying expression and / or secretion of certain cytokines, such as interlekukin-2 (IL-2), interferon-gamma (IFNy), interleukin-1 beta (IL- 1(3), interleukin-4 (IL-4), TNF-alpha (TNFa), interleukin-6 (IL-6), interleukin- 10 (IL-10),217372000540interleukin- 12 (IL- 12), interleukin- 13 (IL- 13), granulocyte-macrophage colony-stimulating factor (GM-CSF), CD 107a, and / or TGF-beta (TGFP). Assays to measure cytokines are well known, and include but are not limited to, ELISA, intracellular cytokine staining, cytometric bead array, RT-PCR, ELISPOT, flow cytometry and bio-assays in which cells responsive to the relevant cytokine are tested for responsiveness (e.g., proliferation) in the presence of a test sample. In some aspects the biological activity can be measured using an animal model of the disease or condition, such as a tumor xenograft model, and assessing the reduction in tumor burden or load and / or survival. In some aspects the biological activity is measured by assessing clinical outcome, such as reduction in tumor burden or load.

[0214] A bispecific antibody provided herein is not limited to any particular bispecific format or method of producing it. Bispecific antibodies can be prepared as full length antibodies or antibody fragments. Among the multispecific antibodies are multispecific single-chain antibodies, e.g., diabodies, triabodies, and tetrabodies, tandem di-scFvs, and tandem tri-scFvs. In some embodiments, the bispecific antibody is formatted as a bivalent antibody. In some embodiments, the bispecific antibody is formatted as a trivalent antibody.

[0215] In some embodiments, each antigen-binding domains, including the anti-CD3 binding domain and the second antigen binding domain, comprise an antibody or an antigenbinding fragment. In some embodiments, the multispecific antibody contains one CD3 binding domain and one second antigen binding domain.

[0216] In some embodiments, the CD3 binding domain includes an antibody or an antigen-binding fragment thereof selected from the group consisting of a Fab fragment, a F(ab')2 fragment, an Fv fragment, an scFv such as a dsFv, a scAb, a dAb, a single domain heavy chain antibody, and a single domain light chain antibody. In some embodiments, the CD3 binding domain is a Fab. In some embodiments, the CD3 binding domain is an scFv, such as a dsFv. In some embodiments, the CD3 binding domain can include any of the antibodies or antigen-binding fragments as described in Section I.A.

[0217] In some embodiments, the second antigen binding domain includes an antibody or an antigen-binding fragment thereof selected from the group consisting of a Fab fragment, a F(ab')2 fragment, an Fv fragment, an scFv such as a dsFv, a scAb, a dAb, a single domain heavy chain antibody, and a single domain light chain antibody. In some embodiments, the second antigen binding domain is a Fab. In some embodiments, the second antigen binding domain is an scFv, such as a dsFv.

[0218] Methods of producing bi-specific T cell engagers are known, including fusion of two different hybridomas (Milstein and Cuello, Nature 1983;305:537-540), chemical217372000540tethering though heterobifunctional cross linkers (Staerz et al. Nature 1985; 314:628-631), manufacturing of scFv-based agents of multivalency and multispecificity by varying the linker length (e.g. U.S. Pat. No. 5,844,094, U.S. Pat. No. 5,837,242 and WO 98 / 44001), diabodies including Dual-Affinity Re-Targeting (DART®) (see, e.g., Moore et al., 2011, Blood 117:4542-51; Veri et al, 2010, Arthritis Rheum 62: 1933-43), and tetravalent and bispecific antibody-like proteins known as DVD-Igs which are engineered from two monoclonal antibodies (Wu, C. et al., Nature Biotechnology, 25, p 1290- 1297, 2007).Exemplary bispecific formats are known, see e.g. Brinkmann et al. MAbs 2017, 9:182-212.

[0219] For instance, among such exemplary bispecific antibodies are bispecific T cell engager (BiTE) molecules, which contain tandem scFv molecules fused by a flexible linker (see e.g. Nagorsen and Bauerle, Exp Cell Res 317, 1255-1260 (2011); tandem scFv molecules fused to each other via, e.g. a flexible linker, and that further contain an Fc domain composed of a first and a second subunit capable of stable association (WO2013026837); diabodies and derivatives thereof, including tandem diabodies (Holliger et al, Prot Eng 9, 299-305 (1996); Kipriyanov et al, J Mol Biol 293, 41-66 (1999)); dual affinity retargeting (DART) molecules that can include the diabody format with a C-terminal disulfide bridge; or triomabs that include whole hybrid mouse / rat IgG molecules (Seimetz et al, Cancer Treat Rev 36, 458-467 (2010); and trivalent bispecific antibodies (e.g. Mayer et al. 2015 Int. J Mol Sci, 16:27497-27507 and U.S. patent publication No. US20200062826).

[0220] Examples of bispecific antibody molecules formats which may be used include (i) a single antibody that has two arms comprising different antigen-binding regions; (ii) a single chain antibody that has specificity to two different epitopes, e.g., via two scFvs linked in tandem by an extra peptide linker; (iii) a dual-variable-domain antibody (DVD-Ig), where each light chain and heavy chain contains two variable domains in tandem through a short peptide linkage (Wu et al., Generation and Characterization of a Dual Variable Domain Immunoglobulin (DVD-Ig™) Molecule, In: Antibody Engineering, Springer Berlin Heidelberg (2010)); (iv) a chemically-linked bispecific (Fab')2 fragment; (v) a Tandab, which is a fusion of two single chain diabodies resulting in a tetravalent bispecific antibody that has two binding sites for each of the target antigens; (vi) a flexibody, which is a combination of scFvs with a diabody resulting in a multivalent molecule; (vii) a so-called “dock and lock” molecule, based on the “dimerization and docking domain” in Protein Kinase A, which, when applied to Fabs, can yield a trivalent bispecific binding protein consisting of two identical Fab fragments linked to a different Fab fragment; (viii) a so-called Scorpion molecule, comprising, e.g., two scFvs fused to both termini of a human Fab-arm; and (ix) a diabody.217372000540

[0221] In some embodiments, bispecific antibodies are bivalent bispecific antibodies. In some embodiments, bivalent bispecific antibody include two antigen binding sites, namely one antigen binding sites for the second antigen and one antigen binding site for CD3. In some embodiments, a bivalent bispecific antibody is monovalent for binding to the second antigen and monovalent for binding to CD3.

[0222] In some embodiments, the bispecific antibody provided herein is composed of a CD3 binding domain that is a fragment of an antibody that specifically binds to CD3, a second antigen binding domain with a fragment of an antibody that specifically binding to a second antigen, and a Fc region. In some embodiments, the CD3 binding domain and the second antigen binding domain are linked via their C-termini to the hinge region of the Fc region. In some embodiments, the Fc region acts to multimerize the two heavy chain polypeptides of the binding molecule. Hence, the Fc region is a multimerization domain. In some embodiments, the Fc region is a heterodimeric Fc region that facilitates formation of a heterodimer containing two different heavy chain polypeptides in the bispecific binding molecule.

[0223] In some embodiments, the bispecific antibody provided herein is composed of a CD3 binding domain that is a Fab fragment of an antibody specifically binding to CD3 (further named also as “CD3-Fab”), a second antigen binding domain with an antibody means for binding to the second antigen, and a Fc region. In some embodiments, the CD3 binding domain and the second antigen binding domain are linked via their C-termini to the hinge region of the Fc part.

[0224] In some embodiments, the bispecific antibody provided herein is composed of a CD3 binding domain that is a scFv fragment, such as a dsFv, specifically binding to CD3 (further named also as “CD3-scFv”, such as “CD3-dsFv”), a second antigen binding domain with an antibody means for binding to the second antigen, and a Fc part. In some embodiments, the CD3 binding domain and the second antigen binding domain are linked via their C-termini to the hinge region of the Fc part.

[0225] In some of any of such embodiments, the bispecific binding molecule, including the anti-CD3 antibody or antigen-binding fragment thereof and / or the second antigen antibody or antigen-binding fragment thereof, comprises at least one post-translational modification of the amino acid sequence. Post-translational modifications can include, e.g., glycosylation, phosphorylation, citrullination, isomerization, ubiquitination, acetylation, hydroxylation, methylation, AMPylation, prenylation, deamidation, eliminylation, carbamylation and carbamoylation. In some embodiments, the post-translational217372000540modification is the modification of an amino acid side chain, such as conversion of an N-terminal amino acid (e.g., glutamate or glutamine) to pyroglutamate. In some such embodiments, this modification occurs at the N-terminus of the heavy chain. In some embodiments, the post-translational modification includes a post-translational modification of a heavy chain N-terminal glutamine (Q) to a pyroglutamate. In some embodiments, in a composition of an antibody or antigen-binding fragment thereof as disclosed herein, such a post-translational modification to pyroglutamate (e.g., at the N-terminus of the heavy chain) is a dominant post-translational modification; in some such embodiments, the antibody or antigen binding fragment thereof in which an N-terminal pyroglutamate is present represents greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, or greater than 95% (w / w) of the antibody or antigen binding fragment thereof in the composition.

[0226] In some embodiments, the post-translational modification is the cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. For instance, an antibody produced by expression of a specific nucleic acid molecule encoding a full-length heavy chain (e.g., by expression in a host cell) may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case where the final two C-terminal amino acids of the heavy chain are glycine and lysine, respectively. Therefore, the C-terminal lysine, or the C-terminal glycine and lysine, of the Fc region may or may not be present. Thus, an antibody may include a heavy chain constant domain with both a C-terminal glycine and lysine, without the C-terminal lysine, or without both the C-terminal glycine and lysine. In some embodiments, in a composition of an antibody or antigen-binding fragment thereof as disclosed herein, glycine cleavage is not a dominant post-translational modification; in some such embodiments, the antibody or antigen binding fragment thereof in which the C-terminal lysine is cleaved from the heavy chain constant domain represents less than 10%, less than 5%, or less than 4% (w / w) of the antibody or antigen binding fragment thereof in the composition. / . Second antigen binding domain

[0227] In certain embodiments, the multispecific antibodies, such as bispecific antibodies, incorporate any of the provided CD3 binding domains, such as anti-CD3 antibodies including antigen-binding fragments, and a second antigen binding domain that has specificity for a second antigen. In some embodiments, the second antigen is an antigen217372000540expressed on a target cell for which targeted killing is desired. For example, the second antigen is a target cell surface antigen.

[0228] In some embodiments, the target cell is an antigen on a B cell, such as an autoreactive B cell or a B cell malignancy. In some embodiments, the B cell antigen is an antigen selected from the group consisting of CD20, CD38, CD22, BAFF-R, and TACI. In some embodiments, the second antigen binding domain binds CD20, CD38, CD22, BAFF-R, or TACI. In some embodiments, the second antigen binding domain is an antibody or antigen binding fragment with means for binding the second antigen (e.g., CD20, CD38, CD22, BAFF-R, and TACI). In some embodiments, such provided binding molecules can be used in methods and uses for treating autoimmune disease. In some embodiments, such provided binding molecules can be used in methods and uses for treating a cancer, such as hematological malignancies or blood cancers, for example leukemia, multiple myeloma (MM) , non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma.

[0229] In some embodiments, the target cell is an antigen on a cancer or tumor cell. In some embodiments, the second antigen is HER2 or EGFR. In some embodiments, such provided binding molecules can be used in methods and uses for treating a cancer.2. Multimerizing domain (e.g., Fc domain)

[0230] Bispecific antigen-binding molecules of the present invention will typically comprise two multimerizing domains, e.g., two Fc domains that are each individually part of a separate antibody heavy chain. The first and second multimerizing domains may be of the same IgG isotype such as, e.g., IgGl / IgGl, IgG2 / IgG2, IgG4 / IgG4. Alternatively, the first and second multimerizing domains may be of different IgG isotypes such as, e.g., IgGl / IgG2, IgGl / IgG4, IgG2 / IgG4, etc.

[0231] Any bispecific antibody format or technology may be used to make the bispecific antigen-binding molecules of the present invention. For example, an antibody or antigenbinding fragment thereof having a first antigen binding specificity can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment having a second antigen-binding specificity to produce a bispecific antigen-binding molecule. Specific exemplary bispecific formats that can be used in the context of the present invention include, without limitation, e.g., scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED) body, leucine zipper,217372000540Duobody, IgGl / IgG2, dual acting Fab (DAF)-IgG, and Mabe bispecific formats (See, for example, Spiess et al. (2015) Mol Immunol 67(2 Pt A):95-106 and Brinkmann et al. (2017) MAbs 9(2): 182-212, and the references cited therein, for a review of the foregoing formats).

[0232] In some embodiments, the bispecific antibody is a full length antibody, such as a full length IgGl antibody. In some embodiments, the full-length IgGl antibody is a full length IgGl, 1 (lambda), K (kappa) antibody or IgGl, K (kappa), K (kappa) antibody. In some embodiments, the full-length antibody includes an Fc region, e.g. composed of at least a hinge region, a CH2 domain, and a CH3 domain.

[0233] In the context of bispecific antigen-binding molecules of the present invention, the multimerizing domains, e.g., Fc domains, may comprise one or more amino acid changes e.g., insertions, deletions or substitutions) as compared to the wild-type, naturally occurring version of the Fc domain.

[0234] In some embodiments, the bispecific antibody is a dimer formed by polypeptides, each containing an Fc region. In some embodiments, the Fc region is formed by Fc domains that are mutated or modified to promote heterodimerization in which different polypeptides can be dimerized to yield a heterodimer. Thus, in some embodiments, the dimer is a heterodimer in which two polypeptide chains of the multispecific polypeptide construct are different. Exemplary modifications to promote heterodimerization are known, including any as described below.

[0235] In one aspect, a bispecific antibody provided herein is composed of a heterodimeric Fc region that facilitates interactions of two different heavy chain polypeptides in which each heavy chain polypeptide contains at least one different binding arm of the bispecific antibody. In some embodiments, the bispecific antibody includes a first heavy chain containing at least one anti-CD3 antibody or antigen-binding fragment and a first polypeptide chain of the heterodimeric Fc and a second heavy chain containing a antigenbinding domain directed against the second antigen and the second polypeptide chain of the heterodimeric Fc. In some embodiments the first polypeptide chain of the heterodimeric Fc-region comprises a first CH3 region, and the second polypeptide chain of the heterodimeric Fc region comprises a second CH3 region, wherein the sequences of the first and second CH3 regions are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions.

[0236] In some embodiments, each polypeptide of an immunoglobulin Fc region comprises a human IgGl polypeptide sequence that is at least 50%, 60%, 65%, 70%, 75%,21737200054080%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 86. In some embodiments, each polypeptide of an immunoglobulin Fc region comprises a human IgGl polypeptide sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 87. In some embodiments, the wild- type Fc region is a wild- type IgGl Fc region comprising the amino acid sequence set forth in SEQ ID NO: 132.

[0237] In the context of the provided disclosure the following notations are, unless otherwise indicated, used to describe a mutation; i) substitution of an amino acid in a given position is written as e.g. T350V which means a substitution of a Threonine in position 350 with a Valine; and ii) for specific variants the specific three or one letter codes are used, including the codes Xaa and X to indicate any amino acid residue. Thus, the substitution of Threonine with Valine in position 350 is designated as: T350V.

[0238] In some embodiments, an IgGl Fc polypeptide or a variant thereof such as any described below can be made in a G1 ml or G1 m3 allotype. In some embodiments, the Fc region can contain amino acids of the human G1 ml allotype, such as residues containing Asp (D) and Feu (L) at positions 356 and 358, e.g. as set forth in SEQ ID NO:87. In some cases, an Fc polypeptide can contain amino acid substitutions E356D and M358L to reconstitute residues of allotype G1 ml. In other embodiments, the Fc region can contain amino acids of the human G1 m3 allotype, such as residues Glu (E) and Met (M) at positions 356 and 358 by EU numbering, e.g. as set forth in SEQ ID NO: 86. In some cases, an Fc polypeptide can contain amino acid substitutions D356E and E358M to reconstitute residues of allotype G1 m3.

[0239] In some embodiments, a bispecific antibody is formatted with an Fc region that lacks a C-terminal Lys (K) residue. In some embodiments, the human IgGl Fc region lacks Lys447 (EU index of Kabat et al 1991 Sequences of Proteins of Immunological Interest).

[0240] In particular embodiments of bispecific antibodies provided herein, the human IgG Fc region is modified to induce heterodimerization. Various methods are known for promoting heterodimerization of complementary Fc polypeptides, see e.g. Ridgway et al, Protein Eng. 9:617-621 (1996); Merchant et al, Nat. Biotechnol. 16(7): 677-81 (1998); Moore et al. (2011) MAbs, 3:546-57; Von Kreudenstein et al. MAbs, (2013) 5:646-54; Gunasekaran et al. (2010) J. Biol. Chem., 285:19637-46; Leaver-Fay et al. (2016) Structure, 24:641-51; Ha et al. (2016) Frontiers in Immunology, 7:1; Davis et al. (2010) Protein Eng Des Sei, 23:195-202; published international PCT Appl. No. WO 1998 / 050431, WO 2009 / 089004,217372000540WO2011143545 WO 2014 / 067011, WO 2012 / 058768, W02018027025; published U.S. patent Appl. No. US20140363426, US20150307628, US20180016354, US20150239991; and U.S. patent Nos. US5731168, US7183076, US9701759, US9605084, and US9650446.Methods to promote heterodimerization of Fc chains include mutagenesis of the Fc region, such as by including a set of “knob-into-hole” mutations or including mutations to effect electrostatic steering of the Fc to favor attractive interactions among different polypeptide chains. For example, in some embodiments, the Fc polypeptides of a heterodimer includes a mutation to alter charge polarity across the Fc dimer interface such that coexpression of electrostatically matched Fc chains support favorable attractive interactions thereby promoting desired Fc heterodimer formation, whereas unfavorable repulsive charge interactions suppress unwanted Fc homodimer formation (Guneskaran et al. (2010) JBC, 285: 19637-19646). When co-expressed in a cell, association between the chains is possible but the chains do not substantially self-associate due to charge repulsion. Other strategies for generating a heterodimeric Fc include mixing human IgG and IgA CH3 domain segments to create a complementary CH3 heterodimer, which is referred to as a SEED Fc.

[0241] Methods and variants for heterodimerization also include those described in published international PCT App. WO2014 / 145806, including “knobs and holes” mutations (also called “skew” variants), mutations that r...

Claims

217372000540CLAIMS WHAT IS CLAIMED:

1. A binding molecule comprising a CD3 binding domain comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein:the VH region comprises a heavy chain complementarity determining region 1 (CDR-Hl) set forth in SEQ ID NO: 107, a heavy chain complementarity determining region 2 (CDR-H2) set forth in SEQ ID NO: 154, and a heavy chain complementarity determining region 3 (CDR-H3) set forth in SEQ ID NO: 109; andthe VL region comprises a light chain complementarity determining region 1 (CDR-Ll) set forth in SEQ ID NO: 19, a light chain complementarity determining region 2 (CDR-L2) set forth in SEQ ID NO: 110, and a light chain complementarity determining region 3 (CDR-L3) set forth within SEQ ID NO: 155.

2. The binding molecule of claim 1, wherein:the VH region comprises a heavy chain complementarity determining region 1 (CDR-Hl) set forth in SEQ ID NO: 107, a heavy chain complementarity determining region 2 (CDR-H2) set forth in SEQ ID NO: 108, and a heavy chain complementarity determining region 3 (CDR-H3) set forth in SEQ ID NO: 109; andthe VL region comprises a light chain complementarity determining region 1 (CDR-Ll) set forth in SEQ ID NO: 19, a light chain complementarity determining region 2 (CDR-L2) set forth in SEQ ID NO: 110, and a light chain complementarity determining region 3 (CDR-L3) set forth within SEQ ID NO: 6.

3. The binding molecule of claim 1 or claim 2, wherein the VH region of the CD3 binding domain and the VL region of the CD3 binding domain comprises, respectively:an amino acid sequence of the consensus sequence set forth in QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2X3GIHWVRQAPGKX4LEWVAAIWYD X5SX6X7YYADSVKGRFTISRDNSX8NTLX9LQMNSLRAEDTAVYYCARSNX10DX11LTX 12X13YX14XI5GXI6XI7VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is Y or H, X4is G or C; X5is G or A or S; X6is K, H, or N, X7is K, T, or D; X8is K, E, or S; X9is Y or D; X10 is Y or F, Xu is I or V, X12 is R or G; X13 is Y or H; X14 is Q or S; X15 is Y or H; Xi6 is I or L; and X17 is N or D; (SEQ ID NO: 156); and217372000540an amino acid sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASX1LEX2G VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX3SYPRTFGX4GTKVEIK, wherein Xi is S or G, X2 is N or S; X3 is K or N; and X4 is Q or C; (SEQ ID NO: 106).

4. The binding molecule of any one of claims 1-3, wherein the VH region of the CD3 binding domain and the VL region of the CD3 binding domain comprises, respectively:an amino acid sequence of the consensus sequence set forth in QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2X3GIHWVRQAPGKX4LEWVAAIWY DX5SX6X7YYADSVKGRFTISRDNSX8NTLX9LQMNSLRAEDTAVYYCARSNX10DX11LT X12X13YX14X15GX16X17VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is Y or H, X4is G or C; X5is G or A or S; X6is K, H, or N, X7is K, T, or D; X8is K, E, or S; X9is Y or D; X10 is Y or F, Xu is I or V, X12 is R or G; X13 is Y or H; X14 is Q or S; X15 is Y or H; Xi6 is I or L; and X17 is N or D; (SEQ ID NO: 105); andan amino acid sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASX1LEX2G VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX3SYPRTFGX4GTKVEIK, wherein XI is S or G, X2 is N or S; X3 is K or N; and X4 is Q or C; (SEQ ID NO: 106).

5. The binding molecule of any one of claims 1-4, wherein:the CDR-H1 comprises the sequence set forth in any one of SEQ ID NOs: 9, 12, 111, or 112, the CDR-H2 comprises the sequence set forth in any one of SEQ ID NOs: 10, 13, 15, 17, or 113-117 , and the CDR-H3 comprises the sequence set forth in any one of SEQ ID NOs: 11, 14, 16, 18, 118-123; andthe CDR-L1 comprises the sequence set forth in SEQ ID NOs: 19, the CDR-L2 comprises the sequence set forth in any one of SEQ ID NOs: 20, 22, 124, or 125, and the CDR-L3 comprises the sequence set forth in any one of SEQ ID NOs: 21 or 23.

6. The binding molecule of any one of claims 1-5, wherein:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;217372000540the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 28, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 42;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 29, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 30, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 31, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 32, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 33, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 34, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;217372000540the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 126, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 4, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 53, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 54, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 55, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 56, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 57, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 58, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;217372000540the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 59, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 60, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 61, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 62, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 63, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 64, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 65, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 66, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 67, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 68, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 69, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;217372000540the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 70, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 71, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 72, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 73, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 74, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 75, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39, 40, or 41;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 40;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 77;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 78;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 79;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 80;217372000540the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39; orthe VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39.

7. The binding molecule of any one of claims 1-6, wherein the VH region of the CD3 binding domain and the VL region of the CD3 binding domain comprises:the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 12, 13, and 11, respectively, and t the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively;the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 14, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively;the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 11, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively;the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 14, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively;the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 16, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively;217372000540the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 17, and 14, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively;the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 18, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the VH region comprises the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 113, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 114, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 115, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 118, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 18, respectively, and VL region the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 119, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 120, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;217372000540the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 16, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 12, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 111, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 112, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 121, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 122, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 123, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 14, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 116, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 117, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;217372000540the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 18, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 119, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 111, 13, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 123, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 23, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 124, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 125, and 23, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 16, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; the CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 12, 13, and 11, respectively, and VL region comprises the CDR-L1, the CDR-L2, and217372000540the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively; orthe CDR-H1, CDR-H2 and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 14, respectively, and VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively.

8. The binding molecule of any one of claims 1-7, wherein in the CD3 binding domain:the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 25, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 26, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 28, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 42;217372000540the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 29, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 30, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 32, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 33, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 34, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35, and the VL region comprises an amino acid sequence that has at217372000540least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 38, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 126, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 4, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 53, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence217372000540identity to SEQ ID NO: 54, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 55, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 56, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 57, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 58, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 59, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 60, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;217372000540the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 61, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 62, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 63, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 64, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 65, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 66, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 67, and the VL region comprises an amino acid sequence that has at217372000540least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 68, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 69, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 70, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 71, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 72, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 73, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence217372000540identity to SEQ ID NO: 74, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 75, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 39, 40, or 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 77;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 76;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 80;217372000540the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39; orthe VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 26, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39.

9. The binding molecule of any one of claims 1-8, wherein in the CD3 binding domain:the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 26 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 27 and 41, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 28 and 42, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 29 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 30 and 41, respectively;217372000540the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 31 and 43, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 32 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 33 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 34 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 35 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 37 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 38 and 41, respectivelythe VH region and the VL region comprise the sequences set forth in SEQ ID NO: 126 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 4 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 83 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 54 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 55 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 56 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 57 and 39, respectively;217372000540the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 58 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 59 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 60 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 61 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 62 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 63 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 64, and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 65 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 66 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 67 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 68 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 69 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 70 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 71 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 72 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 73 and 39, respectively;217372000540the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 74 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 75 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 77, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 41, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 76, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 80, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 27 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 39, respectively; orthe VH region and the VL region comprise the sequences set forth in SEQ ID NO: 26 and 39, respectively.

10. The binding molecule of claim 1, wherein:the VH region comprises a sequence of the consensus sequence set forth in QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD X4SKX5YYADSVKGRFTISRDNSX6NTLX7LQMNSLRAEDTAVYYCARSNYDILTX8X9Y X10X11GX12X13VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is G or C; X4is G or A; X5 is K, T, or D; Xe is K, E, or S; X7 is Y or D; Xs is R or G; X9 is Y or H; X10 is Q or S; Xu is Y or H; X12 is I or L; and X13 is N or D; (SEQ ID NO:7); andthe VL region comprises a sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLEXiGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX2SYPRTFGX3GTKVEIK, wherein Xi is N or S; X2is K or N; X3is Q or C ; (SEQ ID NO:8).21737200054011. The binding molecule of any one of claims 1-10, wherein:the VH region comprises a sequence of the consensus sequence set forth in QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD ASKX4YYADSVKGRFTISRDNSX5NTLYLQMNSLRAEDTAVYYCARSNYDILTX6X7YX 8X9GX10X11VWGQGTTVTVSS, wherein Xi=R or G or E; X2=R or N; X3=G or C; X4=K or T or D; X5=K or E or S; X6=R or G; X7=Y or H; X8=Q or S; X9=Y or H; Xio= I or L; and Xn=N or D (SEQ ID NO: 83); andthe VL region comprises a sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX1SYPRTFGX2GTKVEIK (SEQ ID NO:84), wherein Xi=K or N; X2=Q or C.

12. The binding molecule of any one of claims 1-11, wherein the binding molecule is a bispecific antibody comprising the CD3 binding domain and a second antigen binding domain.

13. A binding molecule comprising a CD3 binding domain and a second antigen binding domain, wherein the binding molecule is bispecific for binding CD3 and the second antigen, wherein:(a) the CD3 binding domain comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein:the VH region comprises a heavy chain complementarity determining region 1 (CDR-Hl) set forth in SEQ ID NO: 1, a heavy chain complementarity determining region 2 (CDR-H2) set forth in SEQ ID NO: 2, and a heavy chain complementarity determining region 3 (CDR-H3) set forth in SEQ ID NOG, andthe VL region comprises a light chain complementarity determining region 1 (CDR-Ll) set forth in SEQ ID NO: 19, a light chain complementarity determining region 2 (CDR-L2) set forth in SEQ ID NO: 5, and a light chain complementarity determining region 3 (CDR-L3) set forth within SEQ ID NO: 6; and(b) the second antigen binding domain comprises a means for binding a second antigen, optionally wherein the second antigen is on a tumor.

14. The binding molecule of claim 13, wherein:217372000540the VH region comprises a CDR-H1 set forth in SEQ ID NO: 1, a CDR-H2 set forth in SEQ ID NO: 85, and a CDR-H3 set forth in SEQ ID NO:3; andthe VL region comprises a CDR-L1 set forth in SEQ ID NO: 19, a CDR-L2 set forth in SEQ ID NO: 22, and a CDR-L3 set forth within SEQ ID NO: 6.

15. The binding molecule of claim 13 or claim 14, wherein:the VH region comprises a sequence of the consensus sequence set forth in QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD X4SKX5YYADSVKGRFTISRDNSX6NTLX7LQMNSLRAEDTAVYYCARSNYDILTX8X9Y X10X11GX12X13VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is G or C; X4is G or A; X5 is K, T, or D; Xe is K, E, or S; X7 is Y or D; Xs is R or G; X9 is Y or H; X10 is Q or S; Xu is Y or H; X12 is I or L; and X13 is N or D; (SEQ ID NO:7); andthe VL region comprising a sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLEXiGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX2SYPRTFGX3GTKVEIK, wherein Xi is N or S; X2is K or N; X3is Q or C ; (SEQ ID NO:8).

16. The binding molecule of claim 15, wherein:the VH region comprises a sequence of the consensus sequence set forth in QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD ASKX4YYADSVKGRFTISRDNSX5NTLYLQMNSLRAEDTAVYYCARSNYDILTX6X7YX 8X9GX10X11VWGQGTTVTVSS, wherein Xi=R or G or E; X2=R or N; X3=G or C; X4=K or T or D; X5=K or E or S; X6=R or G; X7=Y or H; X8=Q or S; X9=Y or H; Xio= I or L; and Xn=N or D (SEQ ID NO: 83); andthe VL region comprises a sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX1SYPRTFGX2GTKVEIK (SEQ ID NO:84), wherein Xi=K or N; X2=Q or C.

17. The binding molecule of any of claims 13-16, wherein the CD3 binding domain binds to CD3 epsilon with a dissociation constant (KD) of 5 nM or more.

18. The binding molecule of any of claims 1-17, wherein the CD3 binding domain binds to CD3 epsilon with a dissociation constant (KD) of 10 nM to 70 nM.21737200054019. The binding molecule of any of claims 1-18, wherein the VH region comprises one or more amino acid residues selected from the group consisting of: an asparagine (N) at position 31 , an alanine (A) at position 55, a tyrosine (Y) at position 80, a glycine (G) at position 106, a histidine (H) at position 107, a serine (S) at position 109, a histidine (H) at position 110, a leucine (L) at position 112, and an aspartic acid (D) at position 113 or any combination thereof, wherein the numbering is relative to SEQ ID NO: 24.

20. The binding molecule of any of claims 1-19, wherein the VH region comprises:(a) amino acid residues asparagine (N) at position 31, alanine (A) at position 55, and tyrosine (Y) at position 80, wherein the numbering is relative to SEQ ID NO: 24;(b) alanine (A) at position 55, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 24; or (c) alanine (A) at position 55, tyrosine (Y) at position 80, serine (S) at position 109, and histidine (H) at position 110, wherein the numbering is relative to SEQ ID NO: 24.

21. The binding molecule of any of claims 1-20, wherein the VL region comprises one or more amino acid residues selected from the group consisting of: a serine (S) at position 56, an asparagine (N) at position 92, and a cysteine (C) at position 100, an asparagine (N) at position 108, or any combination thereof, wherein the numbering is relative to SEQ ID NO: 39.

22. The binding molecule of any of claims 1-21, wherein the VL region comprises:(a) serine (S) at position 56, wherein the numbering is relative to SEQ ID NO:39; or (b) serine (S) at position 56 and asparagine (N) at position 92, wherein the numbering is relative to SEQ ID NO: 39.

23. The binding molecule of any of claims 1-22, wherein the CD3 binding domain exhibits low polyreactivity to extracellular matrix proteins.21737200054024. The binding molecule of claim 23, wherein the CD3 binding domain exhibits an extracellular matrix (ECM) score of less than 14, less than 13, less than 12, less than 11, or less than 10.

25. The binding molecule of any of claims 1-24, wherein the VH region comprises glycine (G) at position 16, a glutamic acid (E) at position 16, a threonine (T) at position 58, an aspartic acid (D) at position 58, a glutamic acid (E) at position 76, a serine (S) at position 76 in relation to SEQ ID NO: 24.26 The binding molecule of any of claims 1-25, wherein the VH region comprises glycine (G) at position 16 and / or threonine (T) at position 58, optionally glycine (G) at position 16 and threonine (T) at position 58 in relation to SEQ ID NO: 24.

27. The binding molecule of any of claims 1-26, wherein the CD3 binding domain is an antigen binding antibody fragment.

28. The binding molecule of claim 27, wherein the CD3 binding domain is a scFv, is a Fab or is an Fv.

29. The binding molecule of claim 27, wherein the second binding domain is an scFv.

30. The binding molecule of any of claims 1-29, wherein the CD3 binding domain is an scFv that is a disulfide-stabilized scFv.

31. The binding molecule of any of claims 1-30, wherein the CD3 binding domain is an scFv that comprises a VH-linker-VL arrangement.

32. The binding molecule of any of claims 1-31, wherein the CD3 binding domain is an scFv that comprises a VL-linker-VH arrangement.

33. The binding molecule of any of claims 1-32, wherein the CD3 binding domain is an scFv that comprises a peptide linker comprising (Gly4Ser)3 (SEQ ID NO: 96).21737200054034. The binding molecule of any of claims 1-24 and 27-33, wherein the VH region of the CD3 binding domain comprises cysteine (C) at position 44 and the VL region of the CD3 binding domain comprises a cysteine (C) at position 100 in relation to SEQ ID NO: 39.

35. The binding molecule of any of claims 1-18, wherein the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within any one of SEQ ID NOs: 24-38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within any one of SEQ ID NOs: 39-43.

36. The binding molecule of any of claims 1-18, wherein:the CDR-H1 comprises the sequence set forth in any one of SEQ ID NOs: 9 or 12, the CDR-H2 comprises the sequence set forth in any one of SEQ ID NOs: 10, 13, 15, or 17, and the CDR-H3 comprises the sequence set forth in any one of SEQ ID NOs: 11, 14, 16, or 18; andthe CDR-L1 comprises the sequence set forth in SEQ ID NOs: 19, the CDR-L2 comprises the sequence set forth in any one of SEQ ID NOs: 20 or 22, and the CDR-L3 comprises the sequence set forth in any one of SEQ ID NOs: 21 or 23.

37. The binding molecule of any of claims 1-18, wherein:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 28, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 42;217372000540the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 29, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 30, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 31, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 32, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 33, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 34, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 41; orthe VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 126, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 40.21737200054038. The binding molecule of any of claims 1-18, wherein:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 12, 13, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 13, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 16, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 17, and 14, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 18, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively.21737200054039. The binding molecule of any of claims 1-18, wherein:the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 24, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 25, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 26, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 28, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 42;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 29, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 30, and the VL region comprises an amino acid sequence that has at217372000540least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 32, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 33, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 34, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence217372000540identity to SEQ ID NO: 37, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 38, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41; orthe VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 126, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40.

40. The binding molecule of any of claims 1-18, wherein:the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 24 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 25 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 26 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 27 and 41, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 28 and 42, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 29 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 30 and 41, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 31 and 43, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 32 and 40, respectively;217372000540the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 33 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 34 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 35 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 37 and 40, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 38 and 41, respectively; orthe VH region and the VL region comprise the sequences set forth in SEQ ID NO: 126 and 40, respectively.

41. The binding molecule of any one of claims 1-40, wherein the second binding domain is an scFv comprising:(a) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 130;(b) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 131;(c) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 128; or(d) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 129.

42. The binding molecule of any one of claims 1-41, wherein the second binding domain is an scFv comprising:(a) the amino acid sequence of SEQ ID NO: 130;(b) the amino acid sequence of SEQ ID NO: 131;217372000540(c) the amino acid sequence of SEQ ID NO: 128; or(d) the amino acid sequence of SEQ ID NO: 129.

43. The binding molecule of claim 1, wherein the CD3 binding domain comprises the VH region that comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 14, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 21, respectively.

44. The binding molecule of claim 43, wherein the CD3 binding domain comprises the VH region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 28, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 42.

45. The binding molecule of claim 43 or claim 44, wherein the CD3 binding domain comprises the VH region and the VL region that comprises the sequence or are the sequence set forth in SEQ ID NO: 28 and 42, respectively.

46. The binding molecule of claim 43, wherein the CD3 binding domain comprises the VH region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 40.

47. The binding molecule of claim 43 or claim 46, wherein the CD3 binding domain comprises the VH region and the VL region that comprises the sequence or are the sequence set forth in SEQ ID NO: 29 and 40, respectively.

48. The binding molecule of claim 1, wherein the CD3 binding domain comprises the VH region that comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOs: 9, 15, and 16, respectively, and the VL region comprises a217372000540CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOs: 19, 22, and 23, respectively.

49. The binding molecule of claim 48, wherein the CD3 binding domain comprises the VH region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 30, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41.

50. The binding molecule of claim 48 or claim 49, wherein the CD3 binding domain comprises the VH region and the VL region that comprises the sequence or are the sequence set forth in SEQ ID NO: 30 and 41, respectively.

51. The binding molecule of claim 48, wherein the CD3 binding domain comprises the VH region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 31, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43.

52. The binding molecule of claim 48 or claim 51, wherein the CD3 binding domain comprises the VH region and the VL region that comprises the sequence or are the sequence set forth in SEQ ID NO: 31 and 43, respectively.

53. The binding molecule of any of claims 1-52, wherein the binding molecule is a full length antibody.

54. The binding molecule of claim 53, wherein the full length antibody comprises a constant region (Fc) from an IgAl, IgA2, IgD, IgE, IgGl, IgG2, IgG3, IgG4, or IgM.

55. The binding molecule of claim 54, wherein the constant region is a human IgGl heavy chain constant region.21737200054056. The binding molecule of claim 54 or 55, wherein the constant region comprises the amino acid sequence set forth in any of SEQ ID NOs: 44-47.

57. The binding molecule of claim 54 or 55, wherein the constant region comprises the amino acid sequence set forth in any of SEQ ID NO: 48-51.

58. A polynucleotide comprising a nucleic acid encoding the binding molecule of any of claims 1-57.

59. A vector comprising the polynucleotide of claim 58.

60. The vector of claim 59, wherein the vector is a viral vector.

61. The vector of claim 60, wherein the viral vector is a retroviral vector or a lentiviral vector.

62. A cell comprising the polynucleotide of claim 58, or the vector of any of claims 59-61.

63. The cell of claim 62, wherein the cell is a mammalian cell.

64. A method of producing an antibody comprising culturing the cell of claim 62 or 63 under a condition that produces the antibody.

65. The method of claim 64, further comprising recovering the antibody produced by the cell.

66. An antibody or antigen-binding fragment thereof produced by the method of claim 64 or claim 65.

67. A composition comprising the binding molecule of any of claims 1-57.

68. The composition of claim 67, further comprising a pharmaceutically acceptable excipient.21737200054069. A method for treating a subject with a disease or condition, the method comprising administering a therapeutically effective amount of the binding molecule of any of claims 1-57.

70. The method of claim 69, wherein the disease or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer.

71. The method of claim 69 or 70, wherein the disease or condition is a tumor or a cancer.

72. The kit comprising the binding molecule of any of claims 1-57 and, optionally, instructions for use.

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